CN101282925A - Management of ophthalmologic disorders, including macular degeneration - Google Patents

Management of ophthalmologic disorders, including macular degeneration Download PDF

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CN101282925A
CN101282925A CNA2006800372332A CN200680037233A CN101282925A CN 101282925 A CN101282925 A CN 101282925A CN A2006800372332 A CNA2006800372332 A CN A2006800372332A CN 200680037233 A CN200680037233 A CN 200680037233A CN 101282925 A CN101282925 A CN 101282925A
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R·R·兰多
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Harvard College
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Abstract

A drag may be used in the preparation of a medicament for the treatment or prevention of an ophthalmologic disorder, wherein the drug inihibits, antagonizes, or short-circuits the visual cycle at a step of the visual cycle that occurs outside a disc of a rod photoreceptor cell.

Description

Treatment to the ophthalmic diseases that comprises macular degeneration
With the mutual reference of related application
[0001] the application requires the right of priority of U.S. Patent Application Serial Number 11/199594 (submission on August 8th, 2005), it is the part continuation application of international application no PCT/US2005/004990 (submission on February 17th, 2005), and this application requires the rights and interests of 60/545456 (submission on February 17th, 2004) of U.S. Provisional Patent Application sequence number, U.S. Provisional Patent Application sequence number 60/567604 (submission on May 3rd, 2004) and U.S. Provisional Patent Application sequence number 60/578324 (submission on June 9th, 2004).Above-mentioned all applications are quoted by complete as reference at this.Statement about federal government's patronage research and development
[0002] supports the part expense of the present application research to provide, authorize to be numbered R01-EY-04096 and/or R01-EY-015425 by NIH.Therefore, United States Government has some rights and interests of the application.
Background of invention
[0003] relevant with age eyesight disease is the significant day by day health problem of industrial society.Age related macular degeneration (AMD) affects millions of people in the world, is the major cause of the aging crowd blurring of image and blinding.In this disease, concentrate on the awl photoreceptor cell death of region of retina foveal, cause eyesight on daytime (eyesight of cone cell control) to be degenerated in time.This disease is lower than 10%, 75 years old above 30% at 50 years old crowd's sickness rate, and the age, big more sickness rate was high more.Lipofuscin accumulation in inside and outside complex compound, toxicity biochemical substances and the RPE of the morbidity of this disease and retinal pigment epithelium (RPE) is associated.The accumulation of these retinal toxicity mixtures is known most important Hazard Factor in the AMD nosetiology.
[0004] RPE has constituted the part of retina-blood barrier, is supporting the function that photosensory cell comprises staff cell and cone cell.In other function, RPE can engulf the acromere of inactivation staff cell routinely.At least in some macular degeneration cases, exactly because this phagolysis has caused the accumulation of lipofuscin among the RPE.The retinal toxicity compound is to form in the membranous disc of shaft-like photosensory cell acromere (disc).At last, the retinal toxicity compound in the membranous disc is transferred among the RPE, and destroys RPE here to further the engulfing of acromere, and causes the RPE apoptosis.Photosensory cell (comprising the cone cell of being responsible for the eyesight on daytime) death then exposes the RPE supporter.
[0005] in the retinal toxicity compound that in staff cell acromere membranous disc, forms, the inferior retinyl-of N--N-retinyl--thanomin (A 2E) being one of them, also is the important component part of retinal toxicity lipofuscin.A 2E generally forms in membranous disc, but because of the too little phagocytic function that can not damage RPE of amount.But, under the particular pathologies condition, A 2E can accumulate in membranous disc too much, causes RPE " poisoning " when engulfing acromere.
[0006] A 2E be by entirely-anti--retinene (one of the intermediate product in rod vision cycle) is transformed.In cycle (as shown in Figure 1), complete-anti--retinene produces in staff cell acromere membranous disc at normal vision.Entirely-anti--retinene can generate the inferior retinyl--PE of N-with Phosphotidyl ethanolamine (PE) (component of membranous disc plasma membrane) reaction.Then by Rim albumen (RmP) (being arranged in ATP-binding cassette transhipment on the staff cell acromere membranous disc) entirely-anti--retinene and/or the inferior retinyl--PE of N-transport out membranous disc and be transported to the cytoplasm of staff cell acromere.Environment there makes the inferior retinyl--PE of N-be easy to hydrolysis.Entirely-anti--retinene is reduced in the staff cell slurry and helps-anti--Vogan-Neu.Then, complete-anti--Vogan-Neu passes shaft-like acromere serous coat and enters ECS and absorbed by retinal pigment epithelium (RPE).Through series reaction, complete-anti--Vogan-Neu is converted into the 11-cis-retinene, and the latter gets back in the photosensory cell and persists in the visual cycle.
[0007] still, the defective of RmP can remove this process that upsets by-anti--retinene complete by stoping from membranous disc.Macular degeneration Si Tajiateshi disease (1/10000 sickness rate in children by name that a kind of recessive form is arranged; In the U.S. 2500 patients are arranged), sudden change has taken place in the gene abcr of the RmP that wherein encodes, makes this transport sub-inactivation.The result causes entirely-and anti--retinene and/or the inferior retinyl--PE of N-be trapped in the membranous disc.Inferior retinyl--the PE of N-can generate the inferior retinyl-of N--N-retinyl--thanomin (A with the complete-anti--retinene reaction of another molecule subsequently 2E), as shown in Figure 2.Also can form some A as mentioned above, even under normal operation 2E; But when its precursor accumulated in membranous disc because of transporting sub-defective, its generation can sharply increase, and then causes macular degeneration.
[0008] macular degeneration of other form also may be by causing lipofuscin cumulative pathology to produce.A kind of principal mode of Si Tajiateshi disease (also is that the relevant autosomal dominant macular dystrophy (ADMD, OMIM#600110)) of a kind of karyomit(e) 6-is to be caused by the transgenation that coding very-long-chain fatty acid-4 (elovl4) extends.
[0009] if having AMD preventive measures that also be seldom, and interventional therapy only the disease form to that determine, comparatively rare is effective.
Summary of the invention
[0010] the present invention relates to treat composition, the system and method for macular degeneration, especially prevent the accumulation of retinal toxicity compound inside and outside retinal pigment epithelium.
[0011] in one embodiment, prevent or reduced A 2The accumulation of E in staff cell acromere membranous disc.Find that the medicine that limits the visual cycle can reduce A 2The generation of E in membranous disc.This restriction can realize by a lot of methods.In one approach, medicine effectively short circuit produce A in the visual cycle 2The part of E precursor (complete-anti--retinene).In another approach, medicine can be blocked entirely synthetic in the visual cycle-anti--necessary particular step of retinene.In another method, medicine can prevent that intermediate product (retinyl ester) from combining with the specific chaperone of retinal pigment epithelium.
[0012] in one embodiment, the method for treatment or prevention experimenter macular degeneration can comprise the medicine that gives to occur in this experimenter's short circuit visual cycle the outer step of shaft-like photosensory cell membranous disc.In another embodiment, the method for treatment or prevention experimenter macular degeneration can comprise give this experimenter can suppress and/or disturb Yelkin TTS retinol acyltransferase, RPE65,11-suitable-retinol dehydrogenase and isomer lytic enzyme at least one medicine.
[0013] in another embodiment, the method of differentiating the macular degeneration medicine can comprise suffering from experimenter's drug candidate that maybe may develop into macular degeneration, detects the accumulation of retinal toxicity compound in this experimenter's retinal pigment epithelium then.
[0014] there is considerable medicine can consider to use.In some embodiments, the visual cycle inhibitor comprises that retinoid is like thing.In the other embodiment, the medicine of energy short circuit visual cycle comprises aromatic amine and hydrazine.
The accompanying drawing summary
[0015] Fig. 1 has described the visual cycle.
[0016] Fig. 2 has described A 2E's is synthetic.
[0017] Fig. 3 has described the intervention of short circuit visual cycle.
[0018] Fig. 4 A-B has shown that TDT (A) and TDH (B) combine with high-affinity with mRPE65.
[0019] Fig. 5 A-B has shown the influence of ERG-b to TDT and TDH.Fig. 5 A has shown the acute effect after intraperitoneal administration 50mg/kg is 1 hour.Fig. 5 B has shown that TDT and TDH are at the continuous action of treatment after 3 days.
[0020] Fig. 6 A-C has shown that certain kinds isoprene mRPE65 antagonist has suppressed the generation of 11-cis-retinene.
[0021] Fig. 7 A-D has shown that certain kinds isoprene mRPE65 antagonist has reduced A 2The accumulation of E.
Detailed Description Of The Invention
[0022] general introduction
[0023] the invention provides by prevention or minimizing A2E is in the accumulation of rhabdocyte acromere membranous disc Treat composition and the method for macular degeneration. Can be complete by reducing in the rhabdocyte acromere membranous disc The amount of-anti--retinene prevents or reduces A2The accumulation of E. In one approach, can press down The medicine of one or more enzymatic steps in visual cycle processed, and then reduce complete-anti--retinene Generation. In another approach, can give to promote 11-cis-retinene isomery among the RPE Turn to the medicine of complete-anti--retinene, thus reduce get back to acromere membranous disc re-isomerization for complete-anti--The amount of the 11-cis-retinene of retinene.
[0024] definition
[0025] for simplicity, before further describing exemplary, with specification, Some term that occurs in embodiment and the accessory claim concentrates on this. These definition should basis Remainder of the present disclosure is understood, and consistent with those skilled in the art's understanding.
[0026] article used herein " " refers to one of this article or (for example at least one more than one Individual) grammar object. For example " a kind of element " refers to a kind of or more than a kind of element.
[0027] " intervention apparatus " be one at the approved term of this technical field and comprise any medicine equipment that can obtain or keep getting involved a certain anatomic region.The professional of medical science and surgical field is familiar with this class apparatus very much.A kind of intervention apparatus may be a needle, conduit, intubate, paracentesis trocar, an a kind of pipe, for example otoscope, masopharyngeal mirror, bronchoscope or other any scope of joint area or any other of being applicable to are suitable for entering predetermined anatomic region or remain on the wherein medicine equipment of a certain position for splitter, a kind of flow diverter or an a kind of scope.
[0028] " biocompatible compound " and " biocompatibility " that uses when referring to some compounds is at the approved term of this technical field.For example, biocompatible compound comprise to host's (for example animal or human's class) do not have toxicity can be in the host yet with the speed degraded (if this degradation) of monomer or oligomer subunit or other by product of toxigenicity concentration.In some embodiments, biological degradation generally comprises this compound at an organic intravital for example monomer whose subunit that is degraded into, and this subunit may be a known non-toxic.But the middle oligomerization product of this degraded gained may have different toxicity, and perhaps biological degradation may comprise oxidizing reaction or other biochemical reaction that produces other molecules outside this compound monomer subunit.Therefore, in certain embodiments, the toxicology of (for example transplant or be injected in the patient body) the biological degradation compound that uses in vivo may need the oxicity analysis of one or many just can determine afterwards.Be not that any purity is that 100% topic is stated composition and all is considered to biocompatible; Really, to state composition must be biocompatible to topic as mentioned above.Therefore, a kind of topic state composition can comprise contain 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or even biocompatible compound still less, for example comprise compound and other material and auxiliary material that the application describes, but still be biocompatibility.
[0029] in order to determine whether physiologically acceptable of a kind of compound or other material, is necessary to carry out oxicity analysis.Such detection is widely known by the people in the present technique field.One of example of this detection can carry out in the cancer cells (for example GT3TKB tumour cell) of living in accordance with the following methods: 37 ℃ of degraded samples are until observing degraded fully in 1M NaOH.Then with 1M HCl this solution that neutralizes.The degraded sample product of about 200 μ L different concns is added in the tissue culturing plate of 96-hole and with 10 4The concentration inoculation gastric carcinoma cells (GT3TKB) in/hole.To degrade sample product and GT3TKB cell incubation 48 hours.Detected result can be mapped to the concentration of degraded sample in the tissue culture hole with allometry per-cent.In addition, can also use detection method assessing compound and preparation in the body that is widely known by the people, for example rat be carried out subcutaneous transplantation and can not cause the stimulation or the inflammation of conspicuous level at the subcutaneous transplantation position to determine them.
[0030] " biodegradable " is the term of present technique field approval, comprises compound, composition and preparation that degraded in use takes place that for example the present invention describes.The difference of common biodegradable compound and non-biodegradation compound is that the former may in use be degraded.This use in certain embodiments comprises uses for example interior therapy of body in the body; This use comprises external use in some other embodiment.In general, the degraded that is attributable to biological degradability comprises that the biodegradable compound degraded generates its composition subunit or this compound is digested the subunit of (for example digesting by a kind of Biochemical processes) Cheng Gengxiao.Can roughly determine two types biological degradation in certain embodiments.For example, one type biological degradation may relate to the fracture of key in this compound (covalent linkage or other).This degraded usually obtains monomer and oligomer, and situation more generally is that this biological degradation causes the bond rupture that connects the one or more subunits of this compound.Opposite is, the biological degradation of another kind of type relates to the key (covalent linkage or other) of side chain inside or the fracture of key that a side chain is connected with this compound.For example a kind of medicine or other may be released by biological degradation with the chemical part that the side chain form is connected with this compound.In certain embodiments, in the process of using a kind of compound biological degradations one or another kind of or two types may appear.As used herein, term " biological degradation " comprises two types biological degradation.
[0031] degradation speed of biodegradable compound is usually got part certainly in various factors, comprises the degree of crosslinking of chemical group, molecular weight, degree of crystallinity, biologically stable and this kind compound of the key relevant with any degraded, physical property, shape and the size of implant and the pattern and the position of administration.For example, molecular weight is big more, degree of crystallinity is high more and/or biologically stable is good more, and the degraded of any biodegradable compound is usually slow more.Term " biodegradable " comprises also material and the process that is known as " can biologically lose and separate ".
[0032] in certain embodiments, if this biodegradable compound also contains a kind of medicine or other relative material, can characterize the biological degradation of this compound by the rate of release of this material.In this case, this biodegradation rate can not only depend on the chemical group character and the physical property of this compound, but also depends on any group property that mixes material wherein.
[0033] in certain embodiments, biological degradation takes place in one section acceptable time in compound formulation in required application.In certain embodiments, therapy in the body for example, this degraded usually with pH be 6 to 8 temperature be 25 to 37 ℃ physiological solution contact back about 5 years, 1 year, six months, three months, one month, 15 days, five days, three days or even one day in generation.In other embodiments, this compound was degraded in the time of about one hour or several weeks, depended on required application.
[0034] term " comprises ", " comprising ", " containing ", " comprising ", " having " and " having " all use with inclusive, open implication, means to comprise additional elements.Term used herein " for example " and " example " are nonrestrictive, only are used for illustration purpose." comprise " and " including but not limited to " replaceable use.
[0035] " administration device " is the term of a present technique field approval, refers to any medicine equipment that is suitable for to target organ or region of anatomy administration.This term comprises and composition can be transported said composition or finishes the apparatus that said composition instils to target organ or anatomic region, even this apparatus is from do not comprise said composition when assembling is made.For example a pin or conduit can be interpreted as a kind of administration device, because described composition can be inserted in anatomic region or blood vessel or other structure relevant with anatomic region by them.Perhaps it can be contained or the surface go up bag by a support of described composition or a splitter or a conduit be interpreted as a kind of administration device.
[0036] when referring to a kind of medicine or other materials, " slowly-releasing " is the term that generally acknowledge in the present technique field.For example a kind ofly the topic that a certain material discharges within a certain period of time can be stated the characteristic that composition may have slowly-releasing, this administration with bolus type is opposite, and the latter makes all doses can be by biological utilisation at one time.For example in indivedual embodiments, at any material (comparing) that may degrade gradually (for example passing through hydrolytic action) with body fluid (comprising blood, tissue juice, lymph liquid etc.) this compound matrix when contacting (being formulated as known other forms of form of the present invention or those skilled in the art of the present technique) and the while is persistent at one section or release wherein comprises in the time of prolongation with the release of injecting agent.This release may prolong the time of releasing of any involved pharmacological agent significant quantity.As described in following detailed content, the slowly-releasing in some embodiment changes to some extent.
[0037] " administration media " is the putative term in present technique field, comprises assisting a kind of medicine or other materials to stride the molecule that cell transmits.The example of administration media comprises: sterol (for example cholesterol) and lipid (for example cation lipid, virion or liposome).
[0038] unless otherwise indicated, the term among the application " perhaps " be interpreted as " and/or ".
[0039] " parenteral admin " and " by the administration of parenteral mode " is the generally acknowledged phrase in present technique field, comprise the administering mode except that enterally administering and topical, for example injection, include, but are not limited in the intravenously, intramuscular, pleura, in the blood vessel, in the pericardium, in the intra-arterial, sheath, in the capsule, interior, intracardiac, the intradermal of eye socket, intraperitoneal, under tracheae, subcutaneous, epidermis, under the intraarticular, capsule, under the arachnoid membrane, in the backbone and breastbone inner injection and transfusion.
[0040] " treatment " is the term that generally acknowledge in the present technique field, comprises inhibition (for example stoping its development) experimenter's certain disease, disorder or illness; With alleviation this disease, disorder or illness (this experimenter is suffered from this disease, disorder or illness by diagnosis), this disease, disorder and/or illness are disappeared.Treat this disease or illness and comprise a kind of symptom of improving this disease or illness at least, even without having influence on the pathologic, physiologic that causes this disease.
[0041] " prevention " is the term that generally acknowledge in the present technique field, comprises that but stoping a kind of disease, disorder or illness to be suffered among the experimenter of these diseases in diagnosis to this disease, disorder and/or illness susceptible takes place.Prevent to diagnose out after this disease but before diagnosing out this illness, prevent the generation of this illness with being included in of a certain disease-related illness.
[0042] " fluid " is the term that generally acknowledge in the present technique field, and it refers to a kind of material of non-solid form, and atom wherein or molecule each other can free movement, for example gas or liquid forms.If unrestricted in use, a kind of fluid materials can flow and fill up residing shape and space, for example covers it and flows out the surface in site or stay dead space under the flap.A kind of fluid materials may be inserted into or inject the limited part in a certain space, flow into then this space bigger partly or entirely.This material is called as " flowable ".This term is that generally acknowledge in the present technique field, for example can be sparged the liquid composition in a certain zone; The available manual liquid composition that the injector to inject of 23G pin for example has been installed or with the liquid composition of catheter drug delivery.Term " flowable " also comprises " gel sample " material that these are at room temperature highly viscous, can from pipe, topple over, be squeezed to expection and use the position, perhaps use any commercially available can provide enough injection pressure with highly viscous material push a kind of drug delivery system for example the injecting apparatus of syringe needle or conduit inject.If the compound itself that uses is flowable, containing this compound compositions does not need to comprise and makes its dispersive biocompatible solvent in body cavity.But can use a kind of drug delivery system that depends on the natural flowability of this material to be applied to required tissue surface so that this fluid compound is transported to body cavity.For example, if a kind of composition that contains fluid compound, can inject said composition make it after injection, form an of short duration biological chemistry barrier or with its bag by internal or tissue, perhaps with its bag by solid portable apparatus.In some example, flowable topic is stated composition can form its place spatial shape under body temperature in for some time.
The resistance to flow that shows when [0043] viscosity is interpreted as a kind of internal friction of flowing material of present technique field approval or a kind of fluid materials generation deformation here.Can be by changing the viscosity of the described compound of molecular-weight adjusting, other methods that can change a certain specific compound physical property all are very common for persons skilled in the art, but are some conventional experimental implementation.The molecular weight of the compound that uses may alter a great deal, and this depends on whether need a kind of hard solid state (more high molecular) or need be in a kind of fluid state (more lower molecular weight).
[0044] " pharmacy is acceptable " is an art-recognized phrase.In certain embodiments, but this term is included in and is suitable for contacting the humans and animals tissue in the rational medical judgment scope and does not have over-drastic toxicity, pungency, anaphylaxis or other problems or complication have composition, compound and other materials and/or the formulation of suitable interests/risk ratio.
[0045] " pharmaceutical acceptable carrier " is art-recognized term, comprise for example pharmacy acceptable material, composition or carrier, for example liquid or solid weighting agent, thinner, auxiliary material, solvent or coating material, these materials all participate in any topic is stated composition transported or be delivered to another organ or health from the part of an organ or health another part.Each carrier all must be that " acceptable " means that other compositions in itself and a kind of composition are compatible not to damage patient.In certain embodiments, pharmaceutical acceptable carrier is pyrogen-free.Some can be used as the pharmaceutical acceptable carrier examples of material and comprise: (1) sugar, for example lactose, dextrose plus saccharose; (2) starch, for example W-Gum and potato starch; (3) Mierocrystalline cellulose and derivative thereof, for example Xylo-Mucine, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) Fructus Hordei Germinatus; (6) gelatin; (7) talcum; (8) auxiliary material, for example theobroma oil and suppository wax; (9) grease, peanut oil for example, Oleum Gossypii semen, sunflower seed oil, sesame oil, sweet oil, Semen Maydis oil and soybean oil; (10) glycol, for example propylene glycol; (11) polyvalent alcohol, for example glycerol, sorbyl alcohol, N.F,USP MANNITOL and polyoxyethylene glycol; (12) ester class, for example ethyl oleate and Laurate ethyl; (13) agar; (14) buffer reagent, for example magnesium hydroxide and aluminium hydroxide; (15) alginic acid; (16) pyrogen-free; (17) isotonic saline solution; (18) ringer's solution; (19) ethanol; (20) other nontoxic compatible compounds that use in phosphoric acid buffer and (21) medicine preparation.
[0046] " pharmaceutically acceptable salt " is art-recognized term, comprises inorganic and organic acid addition salt nontoxic relatively in the composition, includes, but are not limited to medicine, auxiliary material, other materials and other analogues.The example of pharmaceutically acceptable salt comprises mineral acid salt, for example hydrochloride and vitriol; Organic acid salt, for example esilate, benzene sulfonate, tosilate etc.The oxyhydroxide, carbonate and the hydrocarbonate that can the salifiable suitable mineral alkali of shape comprise ammonium, sodium, lithium, potassium, calcium, magnesium, aluminium, zinc etc.Also can be the salt that generates with suitable mineral alkali, comprise and salt nontoxic and that be enough to the salifiable organic bases formation of shape.In order to further specify, these organic basess can comprise list, two and trialkylamine, for example methylamine, dimethylamine and triethylamine; Single, double or trihydroxy-alkanamine, for example single, two or trolamine; Amino acid, for example arginine and Methionin; Guanidine; The N-methylglucosamine; The N-urografic acid methylglucamine salt; L-glutaminate; N methyl piperazine; Morpholine; Quadrol; The N-benzyl-1-phenylethylamine; (trishydroxymethyl) aminomethane and similar substance.For example see J.Pharm.Sci.66:1-19 (1977).
[0047] refers to human or inhuman animal, for example orangutan, Mammals and vertebrates with inscribing " patient ", " experimenter " or " host " that state the method treatment.
[0048] term approved for this area of " preventative or therapeutic " treatment comprises that giving one or more topic of host states composition.If give said composition before bad illness (for example bad illness of other of disease or the host animal) clinical manifestation then this is treated to preventative, for example prevent further developing of the bad illness of host, otherwise, if give said composition after bad illness takes place, then this is treated and is curative (for example being used to reduce, improve or stable existing bad illness or its side effect).
[0049] " medicine ", " medicine ", " medicament " and " biologically active substance " are art-recognized term, comprise that part or general action patient Yu or experimenter are in order to treat the molecule with biology, physiology or pharmacologically active and the other drug of a kind of disease or illness (for example macular degeneration).These terms include, but are not limited to the pharmaceutically acceptable salt and the prodrug of these materials.These medicines may be acidic substance, alkaline matter or salt; They may be ether, ester, acid amides and other similar type when giving patient or experimenter by the prodrug of bioactivation.
[0050] " treatment significant quantity " is art-recognized term.In certain embodiments, this term refers to a certain amount of medicine, can produce the desired effects with interests risk ratio that rational any therapeutic treatment all is suitable for when being contained in a kind of compound.In certain embodiments, this term refers to can eliminate, reduce or keep the essential or competent amount of (for example preventing diffusion) a kind of tumour or other certain treatment plan target spots.Significant quantity may change owing to following factor: by the disease of being treated or illness, certain is given the target structures of medicine, experimenter's volume or the severity of this disease or illness.Those of ordinary skill in the art can rule of thumb come to determine the significant quantity of a certain compound and not necessarily experimentize.In certain embodiments, the intravital treatment significant quantity of a kind of medicine will depend on series of factors, comprise: the speed that a kind of medicine discharges from compound matrix, and this part depends on the chemistry and the physical property of this compound; The chemical group of this medicine; The pattern of administration and method and except that this medicine any and compound matrix bonded other materials.
[0051] " radiosensitizer " is defined as and a kind ofly can strengthens one or more diseases of available electromagnetic radiation treatment or the medicine of treatment of conditions effect when giving with the treatment significant quantity.Generally speaking, radiosensitizer is used in combination the part as preventative or therapeutic treatment with electromagnetic radiation.Those skilled in the art know and can state composition with topic and unite and use the radiosensitizer treat.
[0052] " electromagnetic radiation " used in this explanation includes, but are not limited to wavelength 10 -20The width of cloth to 10m is penetrated.Use the electromagnetic radiation of following type in a certain embodiment of electromagnetic radiation: gamma-radiation (10 -20To 10 -13M), X-radiation (10 -11To 10 -9M), ultraviolet ray (10nm to 400nm), visible light (400nm to 700nm), infrared radiation (700nm to 1.0mm) and microwave radiation (1mm to 30cm).
[0053] " retinol conjugated protein " is the main carrier of alltrans retinol (RBP), and its serum vitamin A content is greater than 90%.RBP is present in serum and relevant with the albumen that cotransports that is known as transthyretin or prealbumin.In cytosol and nucleus, combine (.J.Biol.Chem. such as Folli, Vol.277:41970 with retinol conjugated protein at cytozoic retional and meta-bolites thereof; Ong, etc. (1994) in The Retinoids:Biology, and Chemistry and Medicine (Sporn, M.B., Roberts, A.B., and Goodman, D.S., eds), pp.283-318, Raven Press Ltd., New York; With Li etc. (1996) Annu.Rev.Nutr.16,205).Eyes obviously tend to obtain Vogan-Neu (1. (2002) Biochemistry.41 (51) such as Vogel: 15360) from Vogan-Neu-RBP mixture.BPR family has 7 member: RBP1-7.RBP1 is also referred to as cell RBP1, HGNC:9919, CRABP-I, CRBP, CRBP1 and RBPC, its Nucleotide and aminoacid sequence visible GenBank registration number NM_002899 and NP_002890.RBP2 also is known as cell RBP2, HGNC:9920, CRABP-II, CRBP2, CRBPI and RBPC2, its nucleotide sequence and aminoacid sequence visible GenBank registration number NM_OO4164 and NP_004155.RBP3 is also referred to as matter RBP3, an IRBP, RBPI, D10S64, D10S65 and D10S66, its nucleotide sequence and aminoacid sequence visible GenBank registration number NM_002900 and NP_002891.RBP4 also is known as blood plasma RBP4, its nucleotide sequence and aminoacid sequence visible GenBank registration number NM_006744 and NP_006735.RBP5 also is known as cell RBP5, CRBP3, CRBPIII and CRBP-III, its nucleotide sequence and aminoacid sequence visible GenBank registration number NM_031491 and NP_113679.RBP6 also is known as cellular retinoic acid binding protein 2, cellular retinoic acid binding protein 2, CRABP2, HGNC:2339, CRABP-II, its nucleotide sequence and aminoacid sequence visible GenBank registration number NM_001878 and NP_001869.RBP7 also is known as cell RBP7, HGNC:30316, CRBP4, CRBPIV and MGC70641, its nucleotide sequence and aminoacid sequence visible GenBank registration number NM_052960 and NP_443192.CRBPs is considered to vitamin A is transported to the RBP of eyes.Suppressing other RBPs also can be used for treatment and/or prevents eye disease.
[0054] " whole body administration ", " general administration ", " peripherally administered " and " periphery administration " are art-recognized term, are included in away from being given this topic by the position of treatment sickness influence and state composition or other materials.Directly give medicine or be applied to treat near the disease diseased region, even this medicine finally reaches whole body and distributes, also can be called " part " or " zone " administration.
[0055] " ED 50" be art-recognized term.In certain embodiments, ED 50Finger can produce the drug dose of 50% maximum effect, and perhaps 50% experimenter or preparation produce the dosage of effect." LD 50" be art-recognized term.In certain embodiments, LD 50Guided the dosage of 50% experimenter's death." therapeutic index " is art-recognized term, refers to the therapeutic index of a certain medicine, is defined as LD 50/ ED 50
[0056] when referring to a kind of medicine or a kind of compound (composition for example disclosed herein), " being contained in " or " being encapsulated in " is the term of this area approval.In certain embodiments, these terms comprise this pharmaceutical pack is contained in, is formulated in or be included in a kind of can be in described use-pattern in the composition of this medicine of slowly-releasing.These terms comprise any way that a kind of medicine or other materials is contained in a kind of compound matrix, for example comprise: this compound is a kind of polymkeric substance, this medicine is connected (by covalency or other keying actions) and makes this monomer segment polymerization forming polymer formulations with a monomer of this polymkeric substance, medicine can be distributed in the polymeric matrix, be connected in polymeric matrix surface (by covalency or other keying actions), to be encapsulated in polymeric matrix medium.Term " add altogether " or " packing altogether " refer to state a topic and comprise a kind of medicine or other materials and another medicine or material at least in the composition.
[0057] more specifically, different embodiments Chinese traditional medicine or the other materials packing physical aspect difference to the compound.For example, a kind of medicine or other materials may be at first with the form packing of microballoon, mode and this compound then to have kept a part of micro-sphere structure at least.Perhaps, when a kind of medicine or other materials and the basic unmixing of a kind of controlled release compound, its form with droplet is scattered in rather than it is dissolved in this compound.Any type of packing or comprise the scope that all belongs to disclosure application, any encapsulated medicine or the slowly-releasing of other materials have determined whether the packing form is enough to be applicable to any concrete application.
[0058] " biocompatibility softening agent " is art-recognized term, comprises dissolving in the material that maybe can be scattered in controlled release composition described herein, and it can strengthen the elasticity of this compound matrix and be biocompatible in amount ranges.Suitable softening agent is widely known by the people in this area, comprises United States Patent (USP) 2,784,127 and 4,444,933 disclosed materials.For example ATBC (account for weight 20% or still less), the just own ester of acetyl tributyl citrate three (account for weight 20% or still less), butyl benzyl phthalate, dibutyl phthalate, dioctyl phthalate (DOP), butyryl citric acid tri-n-hexyl ester, dibenzoic diglycol laurate (account for weight 20% or still less) and analogue.
[0059] " small molecules " is the term of this area approval, and in certain embodiments, this term refers to that molecular weight is less than about 2000amu or less than about 1000amu even less than the molecule of 500amu.
[0060] " alkyl " comprises the radical of saturated aliphatic base for the term of this area approval, comprises straight chained alkyl, branched-chain alkyl and cyclic alkyl (alicyclic hydrocarbon), by alkyl cycloalkyl that replaces and the alkyl that is substituted by cycloalkyl.In certain embodiments, the carbochain of straight or branched alkane comprises 30 or still less (for example C1-C30 is a straight chain, and C3-C30 is a side chain) or about 20 or carbon atom still less approximately.Similarly, contain 3 to 10 carbon atoms in the ring structure of naphthenic hydrocarbon approximately, perhaps contain 5,6 or 7 carbon atoms in the ring structure approximately.
[0061] carbonatoms except as otherwise noted, " low alkyl group " refer to contain in a kind of as defined above carbon-chain structure the alkyl of about 10 or about 6 carbon atoms of 1-of 1-.Similarly, " low-grade alkenyl " and " low-grade alkynyl " also has similar chain length.
[0062] " aralkyl " is the term of this area approval, and it refers to a kind of alkyl that is replaced by aryl (for example aryl or heteroaryl).
[0063] " thiazolinyl " and " alkynyl " is the term of this area approval, and they refer to the unsaturated aliphatic base analogue that length is similar and the substituent of abovementioned alkyl, but comprise two keys or triple bond at least respectively.
[0064] " aryl " is the term of present technique field approval, it refers to 5,6 and 7 yuan of monocyclic aromatic bases, can contain 0 to 4 heteroatoms, for example benzene, naphthalene, anthracene, pyrene, pyrroles, furans, thiophene, imidazoles, oxazole, thiazole, triazole, pyrazoles, pyridine, pyrazine, pyridazine and pyrimidine and analogue.Contain heteroatomic aryl in these ring structures and also can be known as " aromatic heterocycle " or " assorted aromatic compound ".This aromatic nucleus may be replaced by above-mentioned substituting group on one or more ring positions, for example halogen, triazo-compound, alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl group, amino, nitro, sulfydryl, imino-(imino), amide group (amido), phosphonate group (phosphonate), phosphonous acid ester group (phosphinate), carbonyl, carboxyl, silyl, ether, alkylthio, alkylsulfonyl, sulfoamido, ketone, aldehyde, ester, heterocycle, fragrance or assorted aromatic portion ,-CF 3,-CN or analogue.Term " fragrance " also comprises the polycyclic system that contains two or more ring structures, wherein two adjacent annulus have two or more carbon atoms (these rings are " condensed ring "), wherein at least one ring is for aromatic nucleus, and another ring may be for example cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocycle.
[0065] ortho position, a position and contraposition are the terms that generally acknowledge in the present technique field, refer to 1 respectively, 2-, 1,3-and 1,4-disubstituted benzene.For example 1,2-dimethylbenzene and ortho-xylene are to agree speech.
[0066] " heterocycle ", " heteroaryl " or " heterocyclic radical " are the terms that generally acknowledge in the present technique field, refer to the 3-10 ring structure, and perhaps 3-7 unit ring comprises 1-4 heteroatoms in their ring structure.Heterocycle also may be many rings.Heterocyclic radical comprises for example thiophene, thianthrene, furans, pyrans, isobenzofuran, chromogen alkene, Xanthene phenothioxin (phenoxanthene), the pyrroles, imidazoles, pyrazoles, isothiazole isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indoles, indazole, purine, quinolizine, isoquinoline 99.9, quinoline, phthalazines, naphthyridines, quinoxaline, quinazoline, cinnolines, pteridine, carbazole, carboline, phenanthridines, acridine, pyrimidine, ferrosin, azophenlyene, phenarsazine, thiodiphenylamine, furazan phenoxazine, tetramethyleneimine, tetrahydrofuran (THF), tetramethylene sulfide oxazole, piperidines, piperazine, morpholine, lactone, lactan is azetidinone and pyrrolidone for example, sultam, sultone and analogue.This heterocycle may be replaced by above-mentioned substituting group in one or more positions, for example halogen, alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfydryl, imino-, amide group, phosphonate group, phosphonous acid ester group, carbonyl, carboxyl, silyl, ether, alkylthio, alkylsulfonyl, ketone, aldehyde, ester, heterocyclic radical, aryl or heteroaryl moieties ,-CF 3,-CN or analogue.
[0067] " polycyclic " or " many cyclic groups " is the term that generally acknowledge in the present technique field, it refers to two or more rings (for example cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl and/or heterocyclic radical), wherein adjoin the total two or more carbon atoms of two rings, for example these rings are " condensed ring ".Be referred to as " bridge " ring by the non-ring that adjoins the carbon atom connection.Each ring of polycyclic all may be replaced by above-mentioned substituting group, for example halogen, alkyl, aralkyl, thiazolinyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfydryl, imino-, amide group, phosphonate group, phosphonous acid ester group, carbonyl, carboxyl, silyl, ether, alkylthio, alkylsulfonyl, ketone, aldehyde, ester, heterocyclic radical, aryl or heteroaryl moieties ,-CF 3,-CN or analogue.
[0068] " carbocyclic ring " is the term that generally acknowledge in the present technique field, it refers to a kind of fragrance or non-aromatic ring, and wherein Huan each atom all is a carbon.
[0069] " nitro " is the generally acknowledged term in present technique field, and it refers to-NO 2" halogen " is the term that generally acknowledge in the present technique field, it refers to-F ,-Cl ,-Br or-I; The term that " sulfydryl " generally acknowledges for the present technique field, it refers to SH; Term " hydroxyl " refers to-OH; The term that " alkylsulfonyl " generally acknowledges for the present technique field, it refers to SO 2-." halogenide " refers to corresponding halide anion, and " senior inorganic chemistry " the Advanced InorganicChemistry " " the 560th page of Cotton and Wilkinson seen in the definition of " pseudohalogen ".
[0070] " amine " and " amino " is the generally acknowledged term in present technique field, and they refer to not have the amine that replaces and replace, the part of for example following general formula representative:
Figure A20068003723300221
Wherein R50, R51 and R52 independently represent a hydrogen, alkyl, thiazolinyl, (CH separately 2) m-R61, or R50 forms the heterocycle that has 4-8 atom in the ring with R51 with the N atom that is connected them; R61 represents an aryl, cycloalkyl, cycloalkenyl group, a heterocycle or encircles one more; M be 0 or scope at the integer of 1-8.In other embodiments, an independent separately hydrogen, alkyl, thiazolinyl, (CH of representing of R50 and R51 (optional and R52) 2) m-R61.Therefore, term " alkylamine " comprises a kind of as defined above amido, has substituted alkyl to be connected with it with no substituted alkyl, promptly at least R50 and R51 one of them be alkyl.The term that " acyl amino " generally acknowledges for the present technique field, it refers to the part of following general formula representative:
Figure A20068003723300231
Wherein R50 as above defines, R54 represent a hydrogen, alkyl, thiazolinyl or-(CH 2) m-R61, wherein m and 1 as above defines.
[0071] " amide group " is the generally acknowledged term in present technique field, refers to the amino carbonyl that replaces and comprises the part that following general formula is represented:
Figure A20068003723300232
Wherein R50 and R51 as above define.Some embodiment of acid amides of the present invention does not comprise unsettled imide.
[0072] term " alkylthio " refers to a kind of alkyl as defined above, and a sulfenyl is coupled.In certain embodiments, should " alkylthio " part can by the S alkyl ,-the S-thiazolinyl ,-the S-alkynyl and-S-(CH 2) mOne of them representative of-R61, wherein m and R61 as above define.Representative alkylthio group comprises methylthio group, ethylmercapto group and analogue.The term that " carboxyl " generally acknowledges for the present technique field comprises the part that following general formula is represented:
Figure A20068003723300233
Wherein X50 is a chemical bond or represents a Sauerstoffatom or a sulphur atom, R55 and R56 represent a hydrogen, alkyl, thiazolinyl ,-(CH 2) m-R61 or a kind of pharmaceutically acceptable salt, R56 represent a hydrogen, alkyl, thiazolinyl or-(CH 2) m-R61, wherein m and R61 as above define.When X50 is a Sauerstoffatom and R55 or R56 when being not hydrogen, this formula representative a kind of " ester ".When X50 is that Sauerstoffatom and R55 as above define, this part refers to a carboxyl here, and especially when R55 was hydrogen, this formula was represented one " carboxylic acid ".When X50 is Sauerstoffatom and R56 when being hydrogen, this formula is represented one " formate ".Generally speaking, when the Sauerstoffatom in the above-mentioned formula was replaced by sulphur atom, this formula was represented one " thiocarbonyl group ".When X50 is sulphur atom and R55 or R56 when being not hydrogen, this formula is represented one " thioesters ".When X50 is sulphur atom and R55 when being hydrogen atom, this formula is represented one " thiocarboxylic acid ".When X50 is sulphur atom and R56 when being hydrogen atom, this formula is represented one " bamic acid ".On the other hand, when X50 is a chemical bond and R55 when being not hydrogen atom, above-mentioned formula is represented " ketone " base.When X50 is a chemical bond and R55 when being hydrogen atom, above-mentioned formula is represented " aldehyde " base.
[0073] term " carbamyl " refers to-O (C=O) NRR ', wherein the independent separately expression hydrogen of R and R ', fatty group, aryl or heteroaryl.
[0074] term " oxo " refer to a kind of ketonic oxygen (=O).
[0075] " oxime " and " oxime ether " is the term that generally acknowledge in the present technique field, and they refer to can be by the part of following general formula representative:
Figure A20068003723300241
Wherein R75 be hydrogen, alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl or-(CH 2) m-R61.When R was H, this part was " oxime "; When R be alkyl, cycloalkyl, thiazolinyl, alkynyl, aryl, aralkyl or-(CH 2) mDuring-R61, this part is an oxime ether.
[0076] " alkoxyl group " or " alkoxyl group " refers to the alkyl as defined above that is connected with an oxygen base for the generally acknowledged term in present technique field.Representative alkoxyl group comprises methoxyl group, oxyethyl group, propoxy-, tert.-butoxy and analogue." ether " refers to that two hydrocarbon polymers and a Sauerstoffatom are covalently bound.Therefore, a kind ofly make substituting group that this alkyl is called ether be exactly or be similar to alkoxyl group, for example group of one of following structure representative :-O-alkyl ,-the O-thiazolinyl ,-the O-alkynyl ,-O-(CH 2) m-R61, wherein m and R61 as above define.
[0077] " sulfonate group (sulfonate) " is the generally acknowledged term in present technique field, and it refers to the part of following general formula representative:
Wherein R57 is a pair of electronics, hydrogen, alkyl, cycloalkyl or aryl.
[0078] " sulfate group (sulfate) " is the generally acknowledged term in present technique field, comprises the part of following general formula representative:
Figure A20068003723300252
Wherein R57 as above defines.
[0079] " sulfoamido (sulfonamido) " is the generally acknowledged term in present technique field, comprises the part of following general formula representative:
Figure A20068003723300253
Wherein R50 and R56 as above define.
[0080] " amino-sulfonyl " is the generally acknowledged term in present technique field, comprises the part of following general formula representative:
Figure A20068003723300254
Wherein R50 and R51 as above define.
[0081] " alkylsulfonyl " is the generally acknowledged term in present technique field, comprises the part of following general formula representative:
Figure A20068003723300261
Wherein R58 is one of following groups: hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl.
[0082] " sulfinyl (sulfoxido) " is the generally acknowledged term in present technique field, and it refers to the part of following general formula representative:
Figure A20068003723300262
Wherein R58 as above defines.
[0083] " phosphoryl " is the term of present technique field approval, is generally the part of following general formula representative:
Figure A20068003723300263
Wherein Q50 represents S or O, and R59 represents hydrogen, a kind of low alkyl group or aryl.When being used for substituting group, for example a kind of alkyl, the phosphoryl of this phosphinylidyne alkyl can be represented by following general formula:
Figure A20068003723300264
Wherein Q50 and R59 are separate, define in foregoing, and Q51 represents O, S and N.When Q50 was S, this phosphoryl partly was " thiophosphatephosphorothioate ".
[0084] " phosphoramidite " is art-recognized term, and can be represented by following general formula:
Figure A20068003723300271
Wherein Q51, R50, R51 and R59 as above define.
[0085] " phosphoramide (phosphonamidite) " also can be represented by following general formula for the generally acknowledged term in present technique field:
Figure A20068003723300272
Wherein Q51, R50, R51 and R59 as above define, and R60 represents a low alkyl group or an aryl.
[0086] can produce the alkenyl or alkynyl of for example amino thiazolinyl, amino alkynyl, amide group thiazolinyl, amide group alkynyl, imino-thiazolinyl, imino-alkynyl, sulfo-thiazolinyl, sulfo-alkynyl, carbonyl substituted with similar substituting group substituted alkenyl and alkynyl.When term alkyl, m, n with similarly phraseology is when the frequency of occurrences surpasses one time in any one structure, the definition in its implication and other part same structures has nothing to do.
[0087] " selenium alkyl " refers to have a substituent alkyl of selenium for the generally acknowledged term in present technique field.Alkyl may substituted example selenium alkyl be selected from as defined above-the Se-alkyl ,-the Se-thiazolinyl ,-the Se-alkynyl and-Se-(CH 2) m-R61, m and R61 as above define.
[0100] trifyl, tosyl group, methylsulfonyl and nine fluorine fourth alkylsulfonyls are the generally acknowledged term in present technique field, and they refer to trifyl, p-toluenesulfonyl, methylsulfonyl and nine fluorine fourth alkylsulfonyls respectively.The term that term triflate, p-toluenesulfonic esters, tosylate and nine fluorine fourth sulphonates are generally acknowledged for the present technique field, they refer to triflate, p-toluenesulfonic esters, methanesulfonates and nine fluorine fourth sulfonate functionality and the molecule that contains described group respectively.
[101] initialism Me, Et, Ph, Tf, Nf, Ts and Ms difference represent methylidene, ethyl, phenyl, trifyl, nine fluorine butyl alkylsulfonyls, p-toluenesulfonyl and methylsulfonyl.All there is the initialism tabulation of using in the more fully common organic chemistry filed first phase of each volume of organic chemistry magazine, and the title of this tabulation is generally the tabulation of standard initialism.
[0102] some compound that is included in the present composition all exists with certain geometry or solid geometry structure.In addition, polymkeric substance of the present invention also may have opticity.The present invention pays close attention to all such compounds and comprises that cis and trans-isomer(ide), R and S enantiomer, diastereo-isomerism, (D)-isomer, (L)-isomer or its racemic mixture and other belong to the mixture in field of the present invention.For example may there be extra asymmetric c atom in substituting group in the alkyl.All these isomer and compounds thereof all belong to category of the present invention.
[0103] a kind of enantiomer of The compounds of this invention if desired can be by asymmetric synthesis or the preparation of chiral auxiliary(reagent) derivatize, and the non-enantiomer mixture that obtains need split and remove auxiliary agent to obtain pure enantiomer.Perhaps, if this molecule contains for example carboxyl of for example amino or acid functional group of basic functions group, can form diastereoisomeric salt with a kind of suitable acid or alkali, separate the diastereoisomeric salt that forms and obtain pure enantiomer by fractional crystallization well known in the art or chromatographic process then with opticity.
Should be understood that [0104] " replacement " or " quilt ... replace " has that this replacements conforms to this valence that is substituted atom and substituting group permission and this replacement can produce this implication of stable compound (for example this compound can not transform automatically, for example rearrangement, cyclisation, elimination or other reactions).
[0105] term " replacement " also comprises the organic compound substituting group that all are feasible.In a general sense, feasible substituting group comprises non-annularity and cyclic substituents, side chain and non-substitution in side chain base, carbocyclic ring and heterocyclic substituent, aromatic nucleus and non-aromatic ring substituting group.Exemplary substituting group comprises group for example described above.Feasible substituting group may be one or more identical or different suitable organic compound.With regard to purpose of the present invention, this heteroatoms for example nitrogen-atoms may have the organic compound substituting group that satisfies the heteroatoms valence that hydrogen replaces and/or any feasible the present invention describes.The present invention is not subjected to any type of restriction of feasible organic compound substituting group.
[0106] 3. composition
[0107] as mentioned above, disturb the visual cycle can treat or prevent macular degeneration by the approach that reduces complete in the shaft-like photosensory cell acromere membranous disc-anti--retinene quantity.The retinal toxicity compound that cone cell produces is inappreciable can ignoring, because staff cell accounts for 95% in all photosensory cells.
[0108] Fig. 1 has described the mammiferous visual cycle.In the stroke of visual cycle, the mixture of 11-cis-retinene and opsin (also being rhodopsin) has experienced a series of biochemical step by the absorption initiation of light.A lot of steps in this cycle are distributed in different zones.As shown in Figure 1, the initial step that absorbs opsin division and form complete-anti--retinene from light occurs in shaft-like photosensory cell acromere membranous disc.Entirely-and anti--retinene is reduced to entirely-and anti--Vogan-Neu occurs in the cytoplasm of staff cell, and steps of all the other generation 11-cis-retinenes occur at retinal pigment epithelium (RPE).
[0109] have at least two kinds of main method can consider to be used for preventing of the accumulation of complete-anti--retinene at membranous disc.In one approach, can suppress one or more enzyme catalysis steps or the chaperone integrating step of visual cycle, and then the approach of complete-anti--retinene is synthesized in blocking-up.In another approach, the part of " short circuit " visual cycle, that is, an early stage intermediate product in the cycle can be divided in the visual cycle in the intermediate product after two or more steps, thereby get around these steps in the cycle, make incomplete-anti--retinene precursor in the membranous disc.A. enzyme inhibitors
[0110] restricted Vogan-Neu can be realized by stoping in the visual cycle arbitrary crucial biochemical reaction in the circulation of visual cycle.Each step in this cycle all may be tackled in this way.Stop an enzyme catalysis step and then make the visual cycle " stop " in RPE, thereby complete-anti--retinene is stayed outside the membranous disc.
[0111] other step in the visual cycle also can stop.For instance, as shown in Figure 1, there is plurality of enzymes to act on entirely-anti--retinene and the derivative when getting back to RPE thereof, comprises LRAT (Yelkin TTS retinol acyltransferase), 11-is suitable-retinol dehydrogenase and IMH (isomer lytic enzyme).In addition, chaperone RPE65 in conjunction with retinyl ester can make those typical hydrophobic compounds through IMH be converted into 11-suitable-Vogan-Neu.These enzymes and chaperone can be used as and suppress and/or the interferential target.
[0112] in certain embodiments; isomer lytic enzyme (IMH) inhibitor; 11-is suitable-the retinol dehydrogenase inhibitor, and Yelkin TTS retinol acyltransferase (LRAT) inhibitor, or retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula I:
Figure A20068003723300301
Wherein, separate when each variable occurs at every turn, n was 0 to 10 (comprising end points); R 1Be hydrogen or alkyl; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; Y is-C (R b) p-,-C (=O)-or-C (R b) pC (=O)-; X is-O-,-N (R a)-,-C (R b) p-or-S-; Z be alkyl, haloalkyl ,-(CH 2CH 2O) pR bOr-C (=O) R bP was 0 to 20 (comprising end points); R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl or haloalkyl;
Figure A20068003723300302
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0113] in certain embodiments; isomer lytic enzyme (IMH) inhibitor; 11-is suitable-the retinol dehydrogenase inhibitor, and Yelkin TTS retinol acyltransferase (LRAT) inhibitor, or retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula II:
Figure A20068003723300303
Wherein, separate when each variable occurs at every turn, n was 0 to 10 (comprising end points);
R 1Be hydrogen or alkyl; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; Y is-C (R b) p-,-C (=O)-or-C (R b) pC (=O)-; X be hydrogen ,-O-,-S-,-N (R a)-,-N (R a)-N (R a)-,-C (=O)-,-C (=NR a)-,-C (=NOH)-,-C (=S)-or-C (R b) p-; Do not exist group Z or Z be hydrogen, alkyl, haloalkyl, aryl, aralkyl ,-CN ,-OR b,-(CH 2CH 2O) pR b,-C (=O) R b,-C (=O) CH 2F ,-C (=O) CHF 2,-C (=O) CF 3,-C (=O) CHN 2,-C (=O) OR b,-C (=O) CH 2OC (=O) R b,-C (=O) C (=O (R b) 2) R b,
Figure A20068003723300311
P was 0 to 20 (comprising end points); R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl;
Figure A20068003723300312
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0114] in certain embodiments; isomer lytic enzyme (IMH) inhibitor; 11-is suitable-the retinol dehydrogenase inhibitor, and Yelkin TTS retinol acyltransferase (LRAT) inhibitor, or retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula III:
Figure A20068003723300313
Wherein, separate when each variable occurs at every turn, n was 0 to 10 (comprising end points); R 1Be hydrogen or alkyl; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; Y is-CR b(OR b)-,-CR b(N (R a) 2)-,-C (=O)-or-C (R b) pC (=O)-; X is-O-,-S-,-N (R a)-,-C (=O)-or-C (R b) p-; Z be hydrogen, alkyl, haloalkyl, aryl, aralkyl ,-OR b,-N (R b) 2,-(CH 2CH 2O) pR b,-C (=O) R b,-C (=NR a) R b,-C (=NOR b) R b,-C (OR b) (R b) 2,-C (N (R a) 2) (R b) 2Or-(CH 2CH 2O) pR bP was 0 to 20 (comprising end points); R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl;
Figure A20068003723300321
Expression singly-bound or trans double bond.
[0115] in certain embodiments; isomer lytic enzyme (IMH) inhibitor; 11-is suitable-the retinol dehydrogenase inhibitor, and Yelkin TTS retinol acyltransferase (LRAT) inhibitor, or retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula VI:
Figure A20068003723300322
Wherein, separate when each variable occurs at every turn, R 1Be hydrogen, alkyl, aryl or aralkyl; X be alkyl, thiazolinyl ,-C (R b) 2-,-C (=O)-,-C (=NR a)-,-C (OH) R bOr-C (N (R a) 2) R b-; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen or alkyl.
[0116] in certain embodiments; isomer lytic enzyme (IMH) inhibitor; 11-is suitable-the retinol dehydrogenase inhibitor, and Yelkin TTS retinol acyltransferase (LRAT) inhibitor, or retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula I:
Wherein, separate when each variable occurs at every turn, n was 0 to 10 (comprising end points); R 1Be hydrogen or alkyl; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; Y is-C (R b) p-,-C (=O)-or-C (R b) pC (=O)-; X is-O-,-N (R a)-,-C (R b) p-or-S-; Z be alkyl, haloalkyl ,-(CH 2CH 2O) pR bOr-C (=O) R bP was 0 to 20 (comprising end points); R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl or haloalkyl;
Figure A20068003723300331
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0117] in certain embodiments, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id:
Figure A20068003723300332
Wherein, separate when each variable occurs at every turn, n was 0 to 4 (comprising end points); R 1Be hydrogen or alkyl; R 3Be hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heteroaralkyl, impure aromatic ene base, hetaryne base, cyano group, nitro, sulfydryl, hydroxyl, alkylsulfonyl, amino, acyl amino, amide group, alkylthio, carboxyl, carbamyl, alkoxyl group, sulfonate group, sulfate group, sulfoamido, sulfamyl, alkylsulfonyl and sulfinyl; There is not R 4Or R 4Be hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heteroaralkyl, impure aromatic ene base, hetaryne base, cyano group, nitro, sulfydryl, hydroxyl, alkylsulfonyl, amino, acyl amino, amide group, alkylthio, carboxyl, carbamyl, alkoxyl group, sulfonate group, sulfate group, sulfoamido, sulfamyl, alkylsulfonyl and sulfinyl; Y is-C (R b) 2-or-C (=O)-; X is-O-,-N (R a)-,-C (R b) 2-or-S-; Z be alkyl, haloalkyl or-C (=O) R bR aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl or haloalkyl;
Figure A20068003723300341
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0118] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, wherein, and R 1Be methyl.
[0119] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, and wherein, n is 0.
[0120] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, and wherein, n is 1.
[0121] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, and wherein, Y is-CH 2-.
[0122] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, and wherein, X is-O-.
[0123] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, and wherein, X is-N (H)-.
[0124] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, and wherein, Z is-C (=O) R b
[0125] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, and wherein, Z is-C (=O) R bAnd R bBe haloalkyl.
[0126] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, and wherein, Z is an alkyl.
[0127] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, and wherein, Z is a haloalkyl.
[0128] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, wherein, and R 3Be hydrogen.
[0129] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ia, Ib, Ic or Id, wherein, and R 4For hydrogen, methyl or there is not R 4Group.
[0130] in certain embodiments, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih:
Figure A20068003723300351
Wherein, separate when each variable occurs at every turn, n was 0 to 4 (comprising end points); R 1Be hydrogen or alkyl; R 3Be hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heteroaralkyl, impure aromatic ene base, hetaryne base, cyano group, nitro, sulfydryl, hydroxyl, alkylsulfonyl, amino, acyl amino, amide group, alkylthio, carboxyl, carbamyl, alkoxyl group, sulfonate group, sulfate group, sulfoamido, sulfamyl, alkylsulfonyl and sulfinyl; X is-O-,-N (R a)-,-C (R b) 2-or-S-; Z be alkyl, haloalkyl or-C (=O) R bR aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl or haloalkyl;
[0131] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, and wherein, n is 0.
[0132] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, and wherein, n is 1.
[0133] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, and wherein, X is-O-.
[0134] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, and wherein, X is-N (H)-.
[0135] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, and wherein, Z is-C (=O) R b
[0136] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, and wherein, Z is-C (=O) R bAnd R bBe haloalkyl.
[0137] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, and wherein, Z is an alkyl.
[0138] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, and wherein, Z is a haloalkyl.
[0139] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, wherein, and R 3Be hydrogen.
[0140] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, and wherein, X is an alkyl for-O-and Z.
[0141] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, and wherein, X is a haloalkyl for-O-and Z.
[0142] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, wherein, X for-N (H)-and Z be alkyl.
[0143] in further embodiment, isomer lytic enzyme (IMH) inhibitor has the structure of formula Ie, If, Ig or Ih, wherein, X for-N (H)-and Z be haloalkyl.
[0144] in one embodiment, isomer lytic enzyme (IMH) inhibitor is 11-suitable-retinyl-bromacetate (cBRA):
Figure A20068003723300371
[0145] in certain embodiments; isomer lytic enzyme (IMH) inhibitor; 11-is suitable-the retinol dehydrogenase inhibitor, and Yelkin TTS retinol acyltransferase (LRAT) inhibitor, or retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula II:
Figure A20068003723300372
Wherein, separate when each variable occurs at every turn, n was 0 to 10 (comprising end points); R 1Be hydrogen or alkyl; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; Y is-C (R b) p-,-C (=O)-or-C (R b) pC (=O)-; X be hydrogen ,-O-,-S-,-N (R a)-,-N (R a)-N (R a)-,-C (=O)-,-C (=NR a)-,-C (=NOH)-,-C (=S)-or-C (R b) p-; Do not have Z group or Z be hydrogen, alkyl, haloalkyl, aryl, aralkyl ,-CN ,-OR b,-(CH 2CH 2O) pR b,-C (=O) R b,-C (=O) CH 2F ,-C (=O) CHF 2,-C (=O) CF 3,-C (=O) CHN 2,-C (=O) OR b,-C (=O) CH 2OC (=O) R b,-C (=O) C (=C (R b) 2) R b,
P was 0 to 20 (comprising end points); R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl;
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0146] in certain embodiments, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId:
Figure A20068003723300381
Wherein, separate when each variable occurs at every turn, n was 0 to 4 (comprising end points); R 1Be hydrogen or alkyl; R 3Be hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heteroaralkyl, impure aromatic ene base, hetaryne base, cyano group, nitro, sulfydryl, hydroxyl, alkylsulfonyl, amino, acyl amino, amide group, alkylthio, carboxyl, carbamyl, alkoxyl group, sulfonate group, sulfate group, sulfoamido, sulfamyl, alkylsulfonyl and sulfinyl; There is not R 4Or R 4Be hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heteroaralkyl, impure aromatic ene base, hetaryne base, cyano group, nitro, sulfydryl, hydroxyl, alkylsulfonyl, amino, acyl amino, amide group, alkylthio, carboxyl, carbamyl, alkoxyl group, sulfonate group, sulfate group, sulfoamido, sulfamyl, alkylsulfonyl and sulfinyl; Y is-C (=O)-or-C (R b) 2-; X be hydrogen ,-O-,-S-,-N (R a)-,-N (R a)-N (R a)-,-C (=O)-,-C (=NR a)-,-C (=NOH)-,-C (=S)-or-C (R b) 2-; Do not have Z group or Z be hydrogen, alkyl, haloalkyl, aryl, aralkyl ,-CN ,-OR b,-C (=O) R b,-C (=O) CH 2F ,-C (=O) CHF 2,-C (=O) CF 3,-C (=O) CHN 2,-C (=O) CH 2OC (=O) R b,-C (=O) OR b,-C (=O) C (=C (R b) 2) R b,
Figure A20068003723300391
R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl;
Figure A20068003723300392
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0147] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, n is 0.
[0148] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, n is 1.
[0149] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, R 1Be hydrogen or methyl.
[0150] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, R 3Be hydrogen.
[0151] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, R 4Be hydrogen or methyl.
[0152] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, Y is-CH 2-
[0153] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, X is-O-.
[0154] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, X is-NH-.
[0155] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, X is-C (R b) 2-.
[0156] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, X is-C (=O)-.
[0157] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, Z is an alkyl.
[0158] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIa, IIb, and IIc, the structure of IId, wherein, Z is a haloalkyl.
[0159] in certain embodiments, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh:
Figure A20068003723300401
Wherein, separate when each variable occurs at every turn, n was 0 to 4 (comprising end points); R 1Be hydrogen or alkyl; R 3Be hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heteroaralkyl, impure aromatic ene base, hetaryne base, cyano group, nitro, sulfydryl, hydroxyl, alkylsulfonyl, amino, acyl amino, amide group, alkylthio, carboxyl, carbamyl, alkoxyl group, sulfonate group, sulfate group, sulfoamido, sulfamyl, alkylsulfonyl and sulfinyl; X be hydrogen ,-O-,-S-,-N (R a)-,-N (R a)-N (R a)-,-C (=O)-,-C (=NR a)-,-C (=NOH)-,-C (=S)-or-C (R b) 2-; Do not have Z group or Z be hydrogen, alkyl, haloalkyl, aryl, aralkyl ,-CN ,-OR b,-C (=O) R b,-C (=O) CH 2F ,-C (=O) CHF 2,-C (=O) CF 3,-C (=O) CHN 2,-C (=O) CH 2OC (=O) R b,-C (=O) OR b,-C (=O) C (=C (R b) 2) R b,
Figure A20068003723300402
R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl;
[0160] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, n is 0.
[0161] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, n is 1.
[0162] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, R 1Be hydrogen or methyl.
[0163] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, R 3Be hydrogen.
[0164] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, R 4Be hydrogen or methyl.
[0165] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, X is-O-.
[0166] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, X is-NH-.
[0167] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, X is-CH 2-.
[0168] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, X is-C (=O)-.
[0169] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, Z is an alkyl.
[0170] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, Z is a haloalkyl.
[0171] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, Z is-C (=O) R b
[0172] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, X be-O-and Z be-C (=O) R b
[0173] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, X is-CH 2-and Z be-C (=O) R b
[0174] in further embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor has formula IIe, IIf, and IIg, the structure of IIh, wherein, X be-NH-and Z be-C (=O) R b
[0175] in one embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor is a 13-demethyl-13,14-dihydro-complete-anti--retinyl-trifluoro-acetate (RFA):
Figure A20068003723300421
[0176] in one embodiment, Yelkin TTS retinol acyltransferase (LRAT) inhibitor is complete-anti--retinyl-alpha bromoisobutyric acid ester.
[0177] in certain embodiments; isomer lytic enzyme (IMH) inhibitor; 11-is suitable-the retinol dehydrogenase inhibitor, and Yelkin TTS retinol acyltransferase (LRAT) inhibitor, or retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula III:
Figure A20068003723300422
Wherein, separate when each variable occurs at every turn, n was 0 to 10 (comprising end points); R 1Be hydrogen or alkyl; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; Y is-CR b(OR b)-,-CR b(N (R a) 2)-,-C (R b) p-,-C (=O)-or-C (R b) pC (=O)-; X is-O-,-S-,-N (R a)-,-C (=O)-or-C (R b) p-; Z be hydrogen, alkyl, haloalkyl, aryl, aralkyl ,-OR b,-N (R b) 2,-(CH 2CH 2O) pR b,-C (=O) R b,-C (=NR a) R b,-C (=NOR b) R b,-C (OR b) (R b) 2,-C (N (R a) 2) (R b) 2Or-(CH 2CH 2O) pR bP was 0 to 20 (comprising end points); R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl;
Figure A20068003723300431
Expression singly-bound or trans double bond.
[0178] in certain embodiments, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, and IIIc, the structure of IIId:
Figure A20068003723300432
Wherein, separate when each variable occurs at every turn, n was 0 to 4 (comprising end points); R 1Be hydrogen or alkyl; Y is-C (=O)-,-CR b(OR b)-,-CR b(N (R a) 2)-or-C (R b) 2-; X is-O-,-S-,-N (R a)-,-C (=O)-or-C (R b) 2-; Z be hydrogen, alkyl, haloalkyl, aryl, aralkyl ,-OR b,-N (R b) 2,-C (=O) R b,-C (=N R a) R b,-C (=NOH) R b,-C (OR b) (R b) 2,-C (N (R a) 2) (R b) 2Or-(CH 2CH 2O) pR bR aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl; P was 0 to 10 (comprising end points);
Expression singly-bound or trans double bond.
[0179] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, and IIIc, the structure of IIId, wherein n is 0.
[0180] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, and IIIc, the structure of IIId, wherein n is 1.
[0181] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, IIIc, the structure of IIId, wherein R 1Be hydrogen or methyl.
[0182] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, IIIc, the structure of IIId, wherein R 3Be hydrogen.
[0183] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, IIIc, the structure of IIId, wherein R 4Be hydrogen or methyl.
[0184] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, and IIIc, the structure of IIId, wherein X is-O-.
[0185] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, and IIIc, the structure of IIId, wherein X is-NH-.
[0186] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, and IIIc, the structure of IIId, wherein X is-C (R b) 2-.
[0187] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, IIIc, the structure of IIId, wherein X be-C (=O)-.
[0188] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, and IIIc, the structure of IIId, wherein Z is an alkyl.
[0189] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III a, IIIb, and IIIc, the structure of IIId, wherein Z is a haloalkyl.
[0190] in certain embodiments, retinal pigment epithelium chaperone (RPE65) antagonist has formula III e, IIIf, and IIIg, the structure of IIIh:
Figure A20068003723300441
Wherein, separate when each variable occurs at every turn, n was 0 to 4 (comprising end points); R 1Be hydrogen or alkyl; X is-O-,-S-,-N (R a)-,-C (=O)-or-C (R b) 2-; Z be hydrogen, alkyl, haloalkyl, aryl, aralkyl ,-OR b,-N (R b) 2,-C (=O) R b,-C (=NR a) R b,-C (=NOH) R b,-C (OR b) (R b) 2,-C (N (R a) 2) (R b) 2Or-(CH 2CH 2O) pR bR aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl; P was 0 to 10 (comprising end points);
[0191] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III e, IIIf, and IIIg, the structure of IIIh, wherein n is 0.
[0192] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III e, IIIf, and IIIg, the structure of IIIh, wherein n is 1.
[0193] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III e, IIIf, IIIg, the structure of IIIh, wherein R 1Be hydrogen or methyl.
[0194] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III e, IIIf, IIIg, the structure of IIIh, wherein Y be-C (=O)-.
[0195] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III e, IIIf, and IIIg, the structure of IIIh, wherein Y is-CH 2-.
[0196] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III e, IIIf, and IIIg, the structure of IIIh, wherein Z is-C (=O) R b
[0197] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III e, IIIf, and IIIg, the structure of IIIh, wherein Z is-CH (OH) R b-.
[0198] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III e, IIIf, and IIIg, the structure of IIIh, wherein Z is CH (NH) R b
[0199] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III e, IIIf, and IIIg, the structure of IIIh, wherein Z is an alkyl.
[0200] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has formula III e, IIIf, and IIIg, the structure of IIIh, wherein Z is a haloalkyl.
[0201] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is 13-suitable-vitamin A acid (isotretinoin, ACCUTANE ):
Figure A20068003723300462
[0202] in certain embodiments, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula IV:
Figure A20068003723300463
Wherein, separate when each variable occurs at every turn, n is 1,2,3 or 4; Y is-C (R b) 2-,-C (=O)-or-OC (=O)-; X is-O-,-NR a-,-C (R b) 2-or-C (=O)-; Z is-C (=O) R b,-OR b,-N (R b) 2, alkyl or haloalkyl; R aBe hydrogen, alkyl, haloalkyl, aryl or aralkyl; R bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl.
[0203] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula IV, and wherein Y is-CH 2-.
[0204] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula IV, and wherein X is-O-.
[0205] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula IV, and wherein Z is-C (=O) R bAnd R bBe alkyl.
[0206] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula IV, and wherein Z is an alkyl.
[0207] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula IV, and wherein Y is-CH 2-, X is-O-, Z is-and C (=O) R bAnd R bBe alkyl.
[0208] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula IV, and wherein Y is-CH 2-, X is-O-that Z is an alkyl.
[0209] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula IV, and wherein Y is-CH 2-, X is-C (=O)-, Z is an alkyl.
[0210] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula IV, and wherein Y is-CH 2-, X is-C (=O)-, Z is-N (R b) 2And R bBe alkyl.
[0211] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is geranyl cetylate (K D=301nM):
Figure A20068003723300471
[0212] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is farnesyl cetylate (K D=63nM)
Figure A20068003723300472
[0213] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is geranyl geranyl cetylate (K D=213nM):
Figure A20068003723300473
[0214] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is geranyl n-Hexadecane ether (K D=416nM):
Figure A20068003723300474
[0215] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is farnesyl n-Hexadecane ether (K D=60nM):
Figure A20068003723300481
[0216] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is geranyl geranyl n-Hexadecane ether (K D=195nM):
Figure A20068003723300482
[0217] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is following compound:
Figure A20068003723300483
[0218] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is following compound (K D=96nM):
Figure A20068003723300484
[0219] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is following compound:
Figure A20068003723300485
[0220] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is following compound (K D=56nM):
Figure A20068003723300486
[0221] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is the farnesyl octanone:
Figure A20068003723300491
[0222] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is an octyl group method acid amides (farnesimide):
Figure A20068003723300492
[0223] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is a hexadecyl method acid amides:
Figure A20068003723300493
[0224] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is following compound (K D=56nM):
Figure A20068003723300494
[0225] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is following compound (K D=58 ± 5nM), called after 13,17,21-trimethylammonium-22 carbon-12,16,20-triolefin-11-ketone or " TDT ":
Figure A20068003723300495
[0226] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is following compound (K D=96 ± 14nM), called after 3,7,11-trimethylammonium-12 carbon-2,6,10-trienic acid palmitamide or " TDH ":
Figure A20068003723300501
[0227] in certain embodiments, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula V:
Figure A20068003723300502
Wherein, separate when each variable occurs at every turn, n is 1,2 or 3; Y is-C (R b) 2-,-C (=O)-or-CH (OH)-; X is-O-,-NR a-or-C (R b) 2-; Z is-C (=O) R b, hydrogen ,-(CH 2CH 2O) pR b, alkyl or haloalkyl; R aBe hydrogen, alkyl, haloalkyl, aryl or aralkyl; R bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl; P was 1 to 10 (comprising end points).
[0228] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula V, and wherein Y is-CH 2-.
[0229] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula V, wherein Y be-C (=O)-.
[0230] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula V, wherein Y be-CH (OH)-.
[0231] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula V, and wherein X is-O-.
[0232] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula V, and wherein X is-NR 3-.
[0233] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula V, and wherein X is-C (R b)-.
[0234] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula V, and wherein Z is an alkyl.
[0235] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula V, and wherein Z is-C (=O) R bAnd R bBe alkyl.
[0236] in further embodiment, retinal pigment epithelium chaperone (RPE65) antagonist has the structure of formula V, and wherein Z is-(CH 2CH 2O) pR bAnd R bBe alkyl.
[0237] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is β-ionoacetyl cetylate (K D=153nM):
Figure A20068003723300511
[0238] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is β-ionoacetyl n-Hexadecane ether (K D=156nM):
Figure A20068003723300512
[0239] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is retinyl-cetylate (4a; K D=47nM):
Figure A20068003723300513
[0240] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is retinyl-capronate (4b; K D=235nM):
Figure A20068003723300514
[0241] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is the retinyl-valerate:
Figure A20068003723300521
[0242] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is retinyl-acetic ester (4c; K D=1,300nM):
Figure A20068003723300522
[0243] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is that hexadecyl is looked yellow ether (4d, K D=25nM):
Figure A20068003723300523
[0244] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is that hexyl is looked yellow ether (K D=151nM):
[0245] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is that methyl is looked yellow ether (K D=24nM):
Figure A20068003723300525
[0246] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is retinyl-[2-(2 '-methoxyl group) oxyethyl group] ether (K D=486nM):
Figure A20068003723300531
[0247] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is:
Figure A20068003723300532
[0248] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is looked yellow acid amides (K for the N-hexadecyl D=40nM):
Figure A20068003723300533
[0249] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is N, and the N-dimethyl is looked yellow acid amides (K D=3,577nM):
Figure A20068003723300534
[0250] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is looked yellow acid amides (K for the N-tertiary butyl D=4,321nM):
Figure A20068003723300535
[0251] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is hexadecyl Vogan-Neu (K D=170nM):
Figure A20068003723300536
[0252] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is the methyl Vogan-Neu:
Figure A20068003723300541
[0253] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is that hexadecyl is looked flavones (K D=64nM):
Figure A20068003723300542
[0254] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is the retinyl-decanone:
Figure A20068003723300543
[0255] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is that methyl is looked flavones (K D=3,786nM):
Figure A20068003723300544
[0256] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is following compound (4e):
Figure A20068003723300545
[0257] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is following compound (4f; K D=64nM)
Figure A20068003723300551
[0258] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is following compound (K D=173nM):
Figure A20068003723300552
[0259] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist be following compound (KD=3,786nM):
Figure A20068003723300553
[0260] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is:
[0261] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is:
Figure A20068003723300555
[0262] in one embodiment, retinal pigment epithelium chaperone (RPE65) antagonist is:
Figure A20068003723300556
[0263] antagonist compound of above-mentioned RPE65, general formula compound and to they various substituent defining and further embodiment also are the LRAT inhibitor simultaneously, at this their are unifiedly come reference as the LRAT inhibitor.
[0264] other RPE65 antagonist and LRAT inhibitor comprise the preparation that suppresses palmitoylation.For example, 2-bromine cetylate can suppress palmitoylation.In some embodiments, the racemic mixture of 2-bromine cetylate can be used to suppress LRAT and/or antagonism RPE65.In other embodiments, (R)-2-bromine palmitinic acid of purifying can be used for suppressing LRAT and/or antagonism RPE65.In other embodiment, (S)-2-bromine palmitinic acid of purifying can be used for suppressing LRAT and/or antagonism RPE65.
[0265] in specific embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VI:
Wherein, separate when each variable occurs at every turn, R 1Be hydrogen, alkyl, aryl or aralkyl; X be alkyl, thiazolinyl ,-C (R b) 2-,-C (=O)-,-C (=NR a)-,-C (OH) R bOr-C (N (R a) 2) R b-; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen or alkyl.
[0266] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VI, wherein R 1Be hydrogen.
[0267] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VI, and wherein X is-C (R b) 2-.
[0268] in further embodiment, 11-is suitable-the retinol dehydrogenase inhibitor has the structure of formula VI, wherein X be-C (=O)-.
[0269] in specific embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VIa or VIb:
Figure A20068003723300571
Wherein, separate when each variable occurs at every turn, R 1Be hydrogen, alkyl, aryl or aralkyl; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; R 3Be hydrogen or alkyl; R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen or alkyl;
Figure A20068003723300572
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0270] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VIa or VIb, wherein R 1Be hydrogen.
[0271] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VIa or VIb, wherein R 2Be alkyl.
[0272] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VIa or VIb, wherein R 3Be hydrogen or methyl.
[0273] in specific embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has formula VIc, the structure of VId or VIe:
Figure A20068003723300573
Wherein, separate when each variable occurs at every turn, n was 1 to 5 (comprising end points); M was 0 to 30 (comprising end points); R 1Be hydrogen, alkyl, aryl or aralkyl; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; R 3Be hydrogen or alkyl; R 4Be hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heteroaralkyl, impure aromatic ene base, hetaryne base, cyano group, nitro, sulfydryl, hydroxyl, alkylsulfonyl, amino, acyl amino, amide group, alkylthio, carboxyl, carbamyl, alkoxyl group, sulfonate group, sulfate group, sulfoamido, sulfamyl, alkylsulfonyl and sulfinyl; R aBe hydrogen, alkyl, aryl or aralkyl; R bBe hydrogen or alkyl;
[0274] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VIc, wherein R 1Be hydrogen.
[0275] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VIc, wherein R 4Be hydrogen.
[0276] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VIc, wherein R 1Be hydrogen and R 4Be hydrogen.
[0277] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VId, and wherein n is 1,2 or 3.
[0278] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VId, wherein R 3Be methyl.
[0279] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VId, wherein R 1Be hydrogen.
[0280] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VId, and wherein n is 1,2 or 3; R 3Be methyl.
[0281] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VId, and wherein n is 1,2 or 3; R 3For methyl and R are hydrogen.
[0282] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VIe, wherein R 1Be hydrogen.
[0283] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VIe, and wherein m was 1 to 10 (comprising end points).
[0284] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VIe, and wherein m was 11 to 20 (comprising end points).
[0285] in further embodiment, 11-is suitable-and the retinol dehydrogenase inhibitor has the structure of formula VIe, and wherein m is 11 to 20 (comprising end points) and R 1Be hydrogen.
[0286] have the 11-of formula VIe representative structure suitable-the retinol dehydrogenase inhibitor can be synthetic according to other method as scheme 1:
Figure A20068003723300591
Scheme 1
[0287] in one embodiment, 11-suitable-the retinol dehydrogenase inhibitor be 13-suitable-vitamin A acid (isotretinoin, ACCUTANE
Figure A20068003723300592
):
Figure A20068003723300593
[0288] comprises that also pharmacy can accept additive salt and have an above-mentioned formula compound complex compound.Have at compound under the situation of one or more chiral centres, if no special instructions, the compound of Kao Lving is the racemic mixture of an independent steric isomer or steric isomer herein.Further comprise prodrug, analogue and their derivative.
[0289] in some embodiments, can unite two or more enzyme inhibitorss of use and/or RPE65 binding inhibitors.In some embodiments, enzyme inhibitors and/or RPE65 binding inhibitors can be united use with the short circuit compound.Can select drug combination to suppress consecutive steps (two steps that take place in succession also promptly) in the visual cycle.
[0290] in certain embodiments, isomer lytic enzyme (IMH) inhibitor is the compound with general formula 1 structure:
Separate when wherein, each variable occurs at every turn: R, R 1, R 2And R 3Be H, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl; W and Y are O, NR, R or S; X is H, alkyl, haloalkyl, aryl or halogenide; M and n are integer 1 to 6 (comprising end points); P is an integer 0 to 6 (comprising end points).
[0291] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, wherein R 2Or R 3Be H or Me.
[0292] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, and wherein m is 2.
[0293] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, and wherein n is 2.
[0294] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, and wherein W is O.
[0295] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, and wherein W is C.
[0296] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, and wherein Y is O.
[0297] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, and wherein p is 1.
[0298] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, and wherein X is Br.
[0299] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, wherein R 2And R 3For H or Me and m are 2.
[0300] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, wherein R 2And R 3For H or Me, m be 2 and n be 2.
[0301] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, wherein R 2And R 3For H or Me, m are 2, n be 2 and W be O.
[0302] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, wherein R 2And R 3For H or Me, m are 2, n is 2, W is that O and Y are O.
[0303] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, wherein R 2And R 3Be H or Me, m is 2, and n is 2, and W is O, and Y is that O and p are 1.
[0304] in further embodiment, the IMH inhibitor has the structure of formula 1 and additional definitions, wherein R 2And R 3Be H or Me, m is 2, and n is 2, and W is O, and Y is O, p be 1 and X be Br.
[0305] in one embodiment, isomer hydrolase inhibitor is 11-suitable-retinyl-bromacetate (cRBA):
Figure A20068003723300611
[0306] in certain embodiments, isomer lytic enzyme (IMH) inhibitor is the compound with formula 8a:
Separate when wherein, each variable occurs at every turn: X is O, S, NR ', CH 2Or NHNR '; Z is O or NOH; R 1For-CH 2F ,-CHF 2,-CF 3,-CH 2N 2,-CH 2C (O) OR ,-OR ' ,-C (O) CHR ' ,-C (NH) CHR ' or-CH=CHR '; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300621
R " ' be CH 3Or H; N is 0,1 or 2; Wherein
Figure A20068003723300622
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0307] compound with formula 8a is considered to the irreversible inhibitor of IMH because they can with the IMH covalent attachment, make it permanent deactivation.
[0308] in certain embodiments, isomer lytic enzyme (IMH) inhibitor is the compound with formula 8a, and wherein Z is O.
[0309] in certain embodiments, isomer lytic enzyme (IMH) inhibitor is the compound with formula 8b:
Separate when wherein, each variable occurs at every turn: Y is C=O, C=S, C=NR ' or CH 2R 1For R ' ,-OR ' or-CN; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300631
R " ' be CH 3Or H; N is 0,1 or 2; Wherein
Figure A20068003723300632
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0310] compound with formula 8b is considered to the reversible inhibitor of IMH, because they can combine with IMH is non-covalent, can not make it permanent deactivation.
[0311] in certain embodiments, isomer lytic enzyme (IMH) inhibitor is the compound with formula 8c:
Figure A20068003723300633
Separate when wherein, each variable occurs at every turn: X is O, S, NR ', CH 2Or NHNR '; Z is O or NOH; R 1For-CH 2F ,-CHF 2,-CF 3,-CH 2N 2,-CH 2C (O) OR ,-OR ' ,-C (O) CHR ' ,-C (NH) CHR ' or-CH=CHR '; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300634
R " ' be CH 3Or H; N is 0,1 or 2.
[0312] compound with formula 8c is considered to the irreversible inhibitor of IMH because they can with the IMH covalent attachment, make it permanent deactivation.
[0313] in certain embodiments, isomer lytic enzyme (IMH) inhibitor is the compound with formula 8c, and wherein Z is O.
[0314] in certain embodiments, isomer lytic enzyme (IMH) inhibitor is the compound with formula 8d:
Figure A20068003723300641
Separate when wherein, each variable occurs at every turn: Y is C=O, C=S, C=NR ' or CH 2R 1For R ' ,-OR ' or-CN; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300642
R " ' be CH 3Or H; N is 0,1 or 2.
[0315] compound with formula 8b is considered to the reversible inhibitor of IMH, because they can combine with IMH is non-covalent, can not make it permanent deactivation.
[0316] in certain embodiments, the LRAT inhibitor is the compound with structure in the general formula 2:
Figure A20068003723300651
Separate when wherein, each variable occurs at every turn: R, R 1, R 2And R 3Be H, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl; W and Y are O, NR, R or S; X is H, alkyl, haloalkyl or aryl; M and n are integer 1 to 6 (comprising end points); P is an integer 0 to 6 (comprising end points).
[0317] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, wherein R 2And R 3Be H or Me.
[0318] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, and wherein m is 3.
[0319] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, and wherein n is 1.
[032] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, and wherein W is O.
[0321] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, and wherein W is C.
[0322] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, and wherein Y is O.
[0323] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, and wherein p is 0.
[0324] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, and wherein X is OCF 3
[0325] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, wherein R 2And R 3For H or Me and m are 3.
[0326] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, wherein R 2And R 3For H or Me, m be 3 and n be 1.
[0327] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, wherein R 2And R 3For H or Me, m are 3, n be 1 and W be O.
[0328] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, wherein R 2And R 3For H or Me, m are 3, n is 1, W is that O and Y are O.
[0329] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, wherein R 2And R 3For H or Me, m are 3, n is 1, W is that O, Y are that O and p are 0.
[0330] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, wherein R 2And R 3For H or Me, m are 3, n is 1, W be O, Y be O, p be 0 and X be OCF 3
[0331] exemplary L RAT inhibitor is complete-anti--retinyl-alpha bromoisobutyric acid ester.Another exemplary L RAT inhibitor is a 13-demethyl-13,14-dihydro-complete-anti--retinyl-trifluoro-acetate (RFA):
Figure A20068003723300661
[0332] in certain embodiments, disturb RPE65 bonded compound can have the structure of general formula 3:
Figure A20068003723300671
Separate when wherein, each variable occurs at every turn: R and R 1Be H, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl or heteroaralkyl; R 2Be H, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl or CO2R; R 3Be H, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl or CH 2OR 4R 4Be H, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclic radical; M is an integer 1 to 6 (comprising end points).
[0333] in further embodiment, the LRAT inhibitor has the structure of formula 3 and additional definitions, wherein R 2For H, Me or-CO 2H.
[0334] in further embodiment, the LRAT inhibitor has the structure of formula 2 and additional definitions, and wherein m is 4.
[0335] in further embodiment, the LRAT inhibitor has the structure of formula 3 and additional definitions, wherein R 3Be H.
[0336] in further embodiment, the LRAT inhibitor has the structure of formula 3 and additional definitions, wherein R 2For H, Me or-CO 2H and m are 4.
[0337] in further embodiment, the LRAT inhibitor has the structure of formula 3 and additional definitions, wherein R 2For H, Me or-CO 2H, m are 4 and R 3Be H.
[0338] in certain embodiments, the LRAT inhibitor can be the compound with formula 6a:
Separate when wherein, each variable occurs at every turn: X is O, S, NR ', CH 2Or NHNR '; Z is O or NOH; R 1For-CH 2F ,-CHF 2,-CF 3,-CH 2N 2,-CH 2C (O) OR ,-OR ' ,-C (O) CHR ' ,-C (NH) CHR ' or-CH=CHR '; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300682
N is 1,2 or 3; Wherein
Figure A20068003723300683
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0339] compound with formula 6a is considered to the irreversible inhibitor of LRAT because they can with the LRAT covalent attachment, make it permanent deactivation.
[0340] in certain embodiments, the LRAT inhibitor can have the structure of formula 6a, and wherein Z is O.
[0341] in certain embodiments, the LRAT inhibitor can have the structure of formula 6b:
Separate when wherein, each variable occurs at every turn: Y is C=O, C=S, C=NR ' or CH 2R 1For R ' ,-OR ' or-CN; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300691
N is 1,2 or 3; Wherein Represent a singly-bound, a cis-double bonds or a trans double bond.
[0342] compound with formula 6c is considered to the reversible inhibitor of LRAT, because they can combine with LRAT is non-covalent, can not make it permanent deactivation.
[0343] in certain embodiments, the LRAT inhibitor is the compound with formula 6c:
Figure A20068003723300693
Separate when wherein, each variable occurs at every turn: X is O, S, NR ', CH 2Or NHNR '; Z is O or NOH; R 1For-CH 2F ,-CHF 2,-CF 3,-CH 2N 2,-CH 2C (O) OR ,-OR ' ,-C (O) CHR ' ,-C (NH) CHR ' or-CH=CHR '; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300694
N is 1,2 or 3.
[0344] compound with formula 6c is considered to the irreversible inhibitor of LRAT because they can with the LRAT covalent attachment, make it permanent deactivation.
[0345] in certain embodiments, the LRAT inhibitor can have the structure of formula 6c, and wherein Z is O.
[0346] in certain embodiments, the LRAT inhibitor can have the structure of formula 6d:
Figure A20068003723300701
Separate when wherein, each variable occurs at every turn: Y is C=O, C=S, C=NR ' or CH 2R 1For R ' ,-OR ' or-CN; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300702
N is 1,2 or 3.
[0347] compound with formula 6d is considered to the reversible inhibitor of LRAT, because they can combine with LRAT is non-covalent, can not make it permanent deactivation.
[0348] one can disturb RPE65 bonded exemplary compounds be 13-suitable-vitamin A acid (isotretinoin, ACCUTANE
Figure A20068003723300703
):
[0349] 13-suitable-vitamin A acid can change into entirely in vivo-anti--vitamin A acid, the latter can suppress the function of RPE65 forcefully.
[0350] in certain embodiments, the RPE65 antagonist is the compound with structure in the general formula 4:
Figure A20068003723300711
Separate when wherein, each variable occurs at every turn: R, R 1, R 2Be H, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxyl group, aryloxy, amino, halogen, hydroxyl or carboxyl; R 3Be alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl or ether; L is H, OH, NH2, N (R) 2, alkoxyl group, aryloxy, halogen, hydroxyl, carboxyl or two L represent O, S or NR together; X is C (R) 2, O, S or NR; M is an integer 1 to 6 (comprising end points).
[0351] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is O.
[0352] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is CH 2
[0353] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is NH.
[0354] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein two L represent O together.
[0355] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein two L represent NOH together.
[0356] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein L is H, OH or NH2.
[0357] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein each L is H.
[0358] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein m is 4.
[0359] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein m is 3.
[0360] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, wherein R 2Be H or methyl.
[0361] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, wherein R 3Be alkyl.
[0362] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, wherein R 3Be ether.
[0363] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is that O and two L represent O together.
[0364] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is that O and each L are H.
[0365] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is that NH and two L represent O together.
[0366] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is CH 2And two L represent O together.
[0367] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is CH 2And two L represent NOH together.
[0368] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is that O, two L represent O, R together 2For H or methyl, m are 4 and R 3It is a pentadecane base.
[0369] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is that O, two L represent O, R together 2For H or methyl, m are 4 and R 3It is one five carbon alkyl.
[0370] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is that O, two L represent O, R together 2For H or methyl, m are 4 and R 3Be methyl.
[0371] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is that O, each L are H, R 2For H or methyl, m are 4 and R 3It is a pentadecane base.
[0372] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is that NH, two L represent O, R together 2For H or methyl, m are 4 and R 3It is a pentadecane base.
[0373] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is CH 2, two L represent O, R together 2For H or methyl, m are 4 and R 3It is a pentadecane base.
[0374] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is that O, each L are H, R 2For H or methyl, m are 4 and R 3Be ether.
[0375] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is that O, each L are H, R 2For H or methyl, m are 4 and R 3For-CH 2OCH 2CH 2OCH 2CH 2OC 7H 15
[0376] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is CH 2, two L represent NOH, R together 2For H or methyl, m are 4 and R 3It is a pentadecane base.
[0377] in further embodiment, the RPE65 antagonist has the structure of formula 4 and additional definitions, and wherein X is CH 2, L is H, OH or NH2, R 2For H or methyl, m are 4 and R 3It is a pentadecane base.
[0378] in certain embodiments, the RPE65 inhibitor is the compound with formula 7a:
Figure A20068003723300731
Separate when wherein, each variable occurs at every turn: X is O, S, NR ', CH 2Or NHNR '; Z is O or NOH; R 1For-CH 2F ,-CHF 2,-CF 3,-CH 2N 2,-CH 2C (O) OR ,-OR ' ,-C (O) CHR ' ,-C (NH) CHR ' or-CH=CHR '; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300741
N is 1,2 or 3; Wherein
Figure A20068003723300742
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0379] compound with formula 7a is considered to the irreversible inhibitor of RPE65 because they can with the RPE65 covalent attachment, make it permanent deactivation.
[0380] in certain embodiments, the RPE65 inhibitor has the structure of formula 7a, and wherein Z is O.
[0381] in certain embodiments, the RPE65 inhibitor has the structure of formula 7b:
Figure A20068003723300743
Separate when wherein, each variable occurs at every turn: Y is O, S, NR ', CH 2=O, C=S, C=NR ', CHOR ', CHNR ' R ", CHSR ' or CH 2R 1For R ' ,-OR ' ,-CN or (CH 2CH 2O) mR '; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R " is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300751
M is 1,2 or 3; N is 1,2 or 3; Wherein
Figure A20068003723300752
Represent a singly-bound, a cis-double bonds or a trans double bond.
[0382] compound with formula 7b is considered to the reversible antagonist of RPE65, because they can combine with RPE65 is non-covalent, can not make it permanent deactivation.
[0383] in certain embodiments, the RPE65 inhibitor is the compound with formula 7c:
Figure A20068003723300753
Separate when wherein, each variable occurs at every turn: X is O, S, NR ', CH 2Or NHNR '; Z is O or NOH; R 1For-CH 2F ,-CHF 2,-CF 3,-CH 2N 2,-CH 2C (O) OR ,-OR ' ,-C (O) CHR ' ,-C (NH) CHR ' or-CH=CHR '; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300754
N is 1,2 or 3.
[0384] compound with formula 7b is considered to the irreversible antagonist of RPE65 because they can with the RPE65 covalent attachment, make it permanent deactivation.
[0385] in certain embodiments, the RPE65 inhibitor has the structure of formula 7c, and wherein Z is O.
[0386] in certain embodiments, the RPE65 inhibitor is the compound with formula 7d:
Figure A20068003723300761
Separate when wherein, each variable occurs at every turn: Y is C=O, C=S, C=NR ', CHOH, CHOR ', NH2, NHR ', NR ' R ", SH, SR ' or CH 2R 1For R ' ,-OR ' ,-CN or-(CH 2CH 2O) mR '; R ' is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R " is H, alkyl, assorted alkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; R is
Figure A20068003723300762
M is 1,2 or 3; N is 1,2 or 3.
[0387] B. short circuit composition
[0388] before the 11-cis-retinene shifts out RPE, by the 11-cis-retinene thermodynamics down isomeric among the catalysis RPE turn to entirely-anti--retinene can realize the short circuit of visual cycle.Fig. 3 has described a kind of intervention.Many materials are applicable to this purposes.In a general sense, suitable medicine comprises anils, i.e. a phenyl ring that has amino side-chain.
[0389] originally, the short circuit molecule can form azomethine with retinene.Isomerization will take place when itself and 11-cis-retinene form azomethine.This process is short circuit.
[0390] the short circuit compound also can be caught retinene, thereby makes them can not form A again 2E and precursor thereof or analogue.For entirely-anti--retinene, can catch it medicine can with the stable azomethine of its formation, thereby prevent that complete-anti--retinene from forming A 2E and similar compound thereof.The short circuit medicine can combine complete-anti--retinene with the kephalin competition.Captive compound can be broken to nontoxic metabolite by N,O-Diacetylmuramidase.A short circuit medicine can disturb the visual cycle by one or both approach, i.e. short circuit 11-cis-retinene and/or catch complete-anti--retinene.(A 2E is the best representative of lipofuscin.Entirely-may also have other condenses-its generation between anti--retinene and the amine (even protein) to cause in conjunction with forming azomethine by active retinene and amine.)
[0391] be that the arylamine/Vogan-Neu schiff bases that is all-trans can continue to form A unexpectedly 2E-sample molecule (because it can at first be degraded), and can more effectively stop this process with short circuit medicine secondary amine.This is because A 2Need a primary amine (two free H) to form two new N-alkyl bonds (each connects a complete-anti--retinene molecule) in the formation mechanism of E, and this process can not take place when initial from secondary amine or tertiary amine.If the short circuit medicine is a secondary amine, it can only be in conjunction with complete-anti--retinene of a part so, and does not have unnecessary position to come in conjunction with second complete-anti--retinene, thereby prevents to form A 2The E analogue, this process as shown in Figure 2.
[0392] the short circuit medicine also can produce long-time effect, therefore needn't frequent drug administration.In some instances, needed be administered once in every month.In other example, need administration weekly.The short circuit medicine is complete by catching-and anti--retinene exhausts the vitamin A of storing in the eyeball effectively.In case the VITAMIN storage will be damaged the visual cycle by drug consumption, delays the formation of lipofuscin, reaches therapeutic purpose.The restock of vitamin A storage is very slowly in the eyeball, and the short circuit medicine that therefore is administered once just can reach long-term effect.In addition, the short circuit medicine is removed comparatively slow from eyeball, so their sustainable effect longer times.
[0393] in certain embodiments, the short circuit compound has the structure of formula VII:
Figure A20068003723300771
Separate when wherein, each variable occurs at every turn: R is H, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl or carbonyl; L is that hydrophobic part or any two adjacent L form thick aromatic ring or hetero-aromatic ring (as: naphthalene, anthracene, indoles, quinoline etc.) together.
[0394] in certain embodiments, separate when each variable occurs at every turn, L is alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, carbonyl, ether or many cyclic groups.In certain embodiments, L has the structure of formula VIIa:
Figure A20068003723300781
Separate when wherein, each variable occurs at every turn: R ' and X are hydrogen, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, carbonyl, alkoxyl group, hydroxyl, sulfydryl, sulfane base or amino; M is an integer 1 to 6 (comprising end points).
[0395] in some embodiments, the short circuit compound has the structure of general formula VIIb:
Figure A20068003723300782
Wherein, n is an integer 1 to 8 (comprising end points).
[0396] in some embodiments, the short circuit compound has the structure of general formula VIIc:
Figure A20068003723300783
Separate when wherein, each variable occurs at every turn: R is H, alkyl or acyl group; R ' is alkyl or ether.
[0397] in further embodiment, the short circuit medicine has the structure of formula VIIc and additional definitions, and wherein two R are H.
[0398] in further embodiment, the short circuit medicine has the structure of formula VIIc and additional definitions, and wherein having a R at least is alkyl.
[0399] in further embodiment, the short circuit medicine has the structure of formula VIIc and additional definitions, and wherein having a R at least is methyl.
[0400] in some embodiments, the short circuit medicine has the structure of general formula VIId:
Figure A20068003723300791
Separate when wherein, each variable occurs at every turn: R is H, alkyl or acyl group; R ' is alkyl or ether.
[0401] in further embodiment, the short circuit medicine has the structure of formula VIId and additional definitions, and wherein two R are H.
[0402] in further embodiment, the short circuit medicine has the structure of formula VIId and additional definitions, and wherein having a R at least is alkyl.
[0403] in further embodiment, the short circuit medicine has the structure of formula VIId and additional definitions, and wherein having a R at least is methyl.
[0404] in some embodiments, the short circuit medicine has the structure of general formula VIIe:
Figure A20068003723300792
Separate when wherein, each variable occurs at every turn: X be hydrogen or-C (=O) OR '; R is H, alkyl or acyl group; R 1Be alkyl.
[0405] in further embodiment, the short circuit medicine has the structure of formula VIIe and additional definitions, and wherein R is H.
[0406] in further embodiment, the short circuit medicine has the structure of formula VIIe and additional definitions, and wherein having a R at least is alkyl.
[0407] in further embodiment, the short circuit medicine has the structure of formula VIIe and additional definitions, and wherein R is a methyl.
[0408] in some embodiments, the short circuit medicine has the structure of general formula VIIf:
Figure A20068003723300801
Separate when wherein, each variable occurs at every turn: R is H, alkyl or acyl group; R ' is an alkyl.
[0409] in further embodiment, the short circuit medicine has the structure of formula VIAnd if additional definitions, and wherein R is H.
[0410] in further embodiment, the short circuit medicine has the structure of formula VIAnd if additional definitions, and wherein having a R at least is alkyl.
[0411] in further embodiment, the short circuit medicine has the structure of formula VIAnd if additional definitions, and wherein R is a methyl.
[0412] in one embodiment, the short circuit medicine is the diamino phenoxy pentane:
[0413] in one embodiment, the short circuit medicine is a phenetidine:
Figure A20068003723300803
[0414] in one embodiment, the short circuit medicine is a tricaine:
Figure A20068003723300811
[0415] in one embodiment, the short circuit medicine is the 4-n-butyl aniline:
[0416] in one embodiment, the short circuit medicine is N-methyl-4-n-butyl aniline:
Figure A20068003723300813
[0417] in one embodiment, the short circuit medicine is ethyl-3-Aminobenzoate:
Figure A20068003723300814
[0418] in one embodiment, the short circuit medicine is ethyl-N-methyl-3-Aminobenzoate:
Figure A20068003723300815
[0419] in one embodiment, the short circuit medicine is ethyl-2-Aminobenzoate:
[0420] in one embodiment, the short circuit medicine is ethyl-N-methyl-2-Aminobenzoate:
Figure A20068003723300821
[0421] in some embodiments, the short circuit medicine has the structure of general formula VIII:
Figure A20068003723300822
Wherein R ' is hydrogen, alkyl or ether; Or any two adjacent L form thick aromatic ring or hetero-aromatic ring (as: naphthalene, anthracene etc.) together.
[0422] in certain embodiments, the short circuit compound has the structure of formula IX:
ANR 2
IX
Separate when wherein, each variable occurs at every turn: R is H, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl or carbonyl; A is optional aryl or the heteroaryl that replaces.
[0423] in some embodiments, the short circuit medicine has the structure of general formula X:
AC(＝O)NHNH 2
X
Separate when wherein, each variable occurs at every turn: R ' is hydrogen, alkyl or ether; A is optional aryl or the heteroaryl that replaces.
[0424] in certain embodiments, the short circuit compound has the structure of general formula 5:
Figure A20068003723300831
Separate when wherein, each variable occurs at every turn: R is H, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl or carbonyl; L is that hydrophobic part or any two adjacent L form thick aromatic ring together; N is an integer 0 to 5 (comprising end points).
[0425] in certain embodiments, separate when each variable occurs at every turn, L is alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, carbonyl, ether or many cyclic groups.In certain embodiments, L has the structure of formula 5a:
Figure A20068003723300832
Separate when wherein, each variable occurs at every turn: R ' and X are H, alkyl, thiazolinyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, carbonyl, alkoxyl group, hydroxyl, sulfydryl, sulfane base or amino; M is an integer 1 to 6 (comprising end points); P is an integer 0 to 5 (comprising end points).
[0426] specific example of picking out from the short circuit medicine comprises the diamino phenoxy pentane:
Phenetidine:
Figure A20068003723300834
Tricaine:
Figure A20068003723300841
[0427] in some embodiments, the short circuit medicine has the structure of general formula 5b: wherein n is an integer 1 to 8 (comprising end points).
Figure A20068003723300842
[0428] in some embodiments, the short circuit medicine has the structure of general formula 5c:
Figure A20068003723300843
Separate when wherein, each variable occurs at every turn: R is H, alkyl or acyl group; And R ' is alkyl or ether.
[0429] in further embodiment, the short circuit medicine has the structure of formula 5c and additional definitions, and wherein two R are H.
[0430] in further embodiment, the short circuit medicine has the structure of formula 5c and additional definitions, and wherein having a R at least is alkyl.
[0431] in further embodiment, the short circuit medicine has the structure of formula 5c and additional definitions, and wherein having a R at least is methyl.
[0432] in some embodiments, the short circuit medicine has the structure of general formula 5c1:
Figure A20068003723300844
Separate when wherein, each variable occurs at every turn: R is H, alkyl or acyl group; R ' is alkyl or ether.
[0433] in further embodiment, the short circuit medicine has the structure of formula 5c1 and additional definitions, and wherein two R are H.
[0434] in further embodiment, the short circuit medicine has the structure of formula 5c1 and additional definitions, and wherein having a R at least is alkyl.
[0435] in further embodiment, the short circuit medicine has the structure of formula 5c1 and additional definitions, and wherein having a R at least is methyl.
[0436] in some embodiments, the short circuit medicine has the structure of general formula 5d:
Figure A20068003723300851
Separate when wherein, each variable occurs at every turn: R is H, alkyl or acyl group; R ' is an alkyl.
[0437] in further embodiment, the short circuit medicine has the structure of formula 5d1 and additional definitions, and wherein R is H.
[0438] in further embodiment, the short circuit medicine has the structure of formula 5d and additional definitions, and wherein having a R at least is alkyl.
[0439] in further embodiment, the short circuit medicine has the structure of formula 5d and additional definitions, and wherein R is a methyl.
[0440] in some embodiments, the short circuit medicine has the structure of general formula 5d1:
Figure A20068003723300852
Separate when wherein, each variable occurs at every turn: R is H, alkyl or acyl group; R ' is an alkyl.
[0441] in further embodiment, the short circuit medicine has the structure of formula 5d1 and additional definitions, and wherein R is H.
[0442] in further embodiment, the short circuit medicine has the structure of formula 5d1 and additional definitions, and wherein having a R at least is alkyl.
[0443] in further embodiment, the short circuit medicine has the structure of formula 5d1 and additional definitions, and wherein R is a methyl.
[0444] in some embodiments, the short circuit medicine has the structure of general formula 5e:
Figure A20068003723300861
Wherein R ' is alkyl or ether.
[0445] with preventing that vitamin A from entering the preparation of eyeball or medicine also can be treated or prevention and the relevant disease of lipofuscin accumulation.Example formulation is for preventing the medicine by the vitamin A transhipment of retinol conjugated protein (RBP) mediation.Therefore preparation is RBP inhibitor or blocker.RBP is CRBP albumen ((1994) Nutr.Rev.52:524 such as Ong and Cowan etc. (1993) J.MoI.Biol.230:1225) or serum RBP ((1984) EMBO such as Blomhoff etc. (1990) Science 250:399 and Newcomer J.3,1451).The preferred RBP that suppresses is CRBP-1.In an exemplary, the RBP blocker is the fenretinide analogue of fenretinide, non--retinoid or the fenretinide isoprenoid of non--retinoid.Example compound has the structure of describing among the formula XI:
Figure A20068003723300862
Wherein, separate when each variable occurs at every turn, n was 0 to 10 (comprising end points); R 1Be hydrogen or alkyl; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; Z be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, aralkyl ,-C (=O) R bOr-(CH 2) pR bP was 0 to 20 (comprising end points); R aBe hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; R bBe hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl;
Figure A20068003723300871
Expression singly-bound or trans double bond.
[0446] the RBP blocker has the structure of XI, wherein R in further embodiment 1Be hydrogen or methyl.
[0447] the RBP blocker has the structure of XI in further embodiment, and wherein Z is an aryl.
[0448] the RBP blocker has the structure of XI, wherein R in further embodiment aBe hydrogen.
[0449] the RBP blocker has the structure of XI, wherein R in further embodiment 1For hydrogen or methyl, Z are aryl and R aBe hydrogen.
[0450] the RBP blocker among the present invention in another embodiment has the structure of formula XIa:
Wherein, separate when each variable occurs at every turn, n was 0 to 10 (comprising end points); R 1Be hydrogen or alkyl; R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; R 3, R 4, R 5, R 6And R 7Be hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heteroaralkyl, impure aromatic ene base, hetaryne base, cyano group, nitro, sulfydryl, hydroxyl, alkylsulfonyl, amino, acyl amino, amide group, sulfane base, carboxyl, carbamyl, alkoxyl group, sulfonate group, sulfate group, sulfoamido, sulfamyl, alkylsulfonyl or sulfinyl; R 3Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl;
Figure A20068003723300881
Expression singly-bound or trans double bond.
[0451] the RBP blocker has the structure of XIa, wherein R in further embodiment 1Be hydrogen or methyl.
[0452] the RBP blocker has the structure of XIa, wherein R in further embodiment aBe hydrogen.
[0453] the RBP blocker has the structure of XIa, wherein R in further embodiment 1Be hydrogen or methyl and R aBe hydrogen.
[0454] the RBP blocker has the structure of XIa, wherein R in further embodiment 3, R 4, R 6And R 7Be hydrogen.
[0455] the RBP blocker has the structure of XIa, wherein R in further embodiment 5Be hydroxyl.
[0456] the RBP blocker has the structure of XIa, wherein R in further embodiment 3, R 4, R 6And R 7Be hydrogen and R 5Be hydroxyl.
[0457] the RBP blocker has the structure of XIa, wherein R in further embodiment 1Be hydrogen or methyl; R aBe hydrogen; R 3, R 4, R 6And R 7Be hydrogen and R 5Be hydroxyl.
[0458] the RBP blocker among the present invention in another embodiment has the structure of formula XIb:
Wherein, separate when each variable occurs at every turn, n was 0 to 5 (comprising end points); R 1Be hydrogen or methyl; R 2For hydrogen, alkyl, thiazolinyl, alkynyl, aryl,
R 3, R 4, R 5, R 6, R 7And R 8Be hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heteroaralkyl, impure aromatic ene base, hetaryne base, cyano group, nitro, sulfydryl, hydroxyl, alkylsulfonyl, amino, acyl amino, amide group, sulfane base, carboxyl, carbamyl, alkoxyl group, sulfonate group, sulfate group, sulfoamido, sulfamyl, alkylsulfonyl or sulfinyl; Any two paired R 8Can form C (=O) R with the carbon that links to each other with them aBe hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl.
[0459] the RBP blocker has the structure of XIb, wherein R in further embodiment 1Be hydrogen or methyl.
[0460] the RBP blocker has the structure of XIb, wherein R in further embodiment aBe hydrogen.
[0461] the RBP blocker has the structure of XIb, wherein R in further embodiment 1Be hydrogen or methyl and R aBe hydrogen.
[0462] the RBP blocker has the structure of XIb, wherein R in further embodiment 3, R 4, R 6And R 7Be hydrogen.
[0463] the RBP blocker has the structure of XIb, wherein R in further embodiment 5Be hydroxyl.
[0464] the RBP blocker has the structure of XIb, wherein R in further embodiment 3, R 4, R 6And R 7Be hydrogen and R 5Be hydroxyl.
[0465] the RBP blocker has the structure of XIb, wherein R in further embodiment 1Be hydrogen or methyl; R aBe hydrogen; R 3, R 4, R 6And R 7Be hydrogen and R 5Be hydroxyl.
[0466] the RBP blocker has the structure of XIb in further embodiment, and wherein n was 1 to 3 (comprising end points).
[0467] the RBP blocker has the structure of XIb, wherein R in further embodiment 2For
Figure A20068003723300901
[0468] the RBP blocker has the structure of XIb, wherein R in further embodiment 2For
Figure A20068003723300902
[0469] the RBP blocker has the structure of XIb, wherein R in further embodiment 2For
Figure A20068003723300903
[0470] the fenretinide analogue that the inhibition compound of RBP can right and wrong-retinoid, for example above-mentioned those compounds, analogue wherein are not fenretinides.
[0471] disturb the plasma membrane acceptor of halo-RBP also can suppress vitamin A and be transported to eyeball, this process has been in the news and has been present in ((1999) such as Vogel that J.18:4633 Quadro etc. (1999) EMBO quotes) among the RBP.Perhaps can suppress the contact between RBP and the acceptor thereof.
[0472] in another embodiment, (for example can adopt the retinyl ester isomerase inhibitors, 11-is suitable-the retinyl-bromacetate) and/or cell retinaldehyde binding protein (CRALBP) inhibitor (for example, suitable-isoprenoid) and/or 11-suitable-retinol dehydrogenase (for example, pyrazoles).
[0473] also comprises the complex compound that pharmacy can be accepted additive salt and have above-mentioned formula compound.Have at compound under the situation of one or more chiral centres, if no special instructions, the compound of Kao Lving is the racemic mixture of an independent steric isomer or steric isomer herein.Also further comprise prodrug, analogue and their derivative.
[0474] in some embodiments, give the experimenter one or more combination of compounds described herein.Two or more short circuit compounds can be united use.In some embodiments, an enzyme inhibitors and/or RPE65 binding inhibitors and a short circuit compound can be united use.Also an enzyme inhibitors and/or short circuit compound and one or more prevention vitamin A can be transported into the preparation of eyeball and be united use, for example fenretinide, non--retinoid fenretinide analogue and non--retinoid isoprene.For example, can accept the compound of experimenter's formula XI of the compound of formula formula I, II, III, IV, V, VI, VII, VIII, IX or X.Can also use the arbitrary combination that acts on the different target proteinate.
[0475] can accept to be selected from N-(4-hydroxyphenyl) and look the C-glucosides of yellow acid amides-O-glucuronide and aryl amide experimenter's a kind of compound described herein like the compound of thing; for example; the compound of a kind of formula XI; the former includes but not limited to 4-(looking yellow amide group) phenyl-C-glucuronide; 4-(looking yellow amide group) phenyl-C-glucoside; 4-(looking yellow amide group) phenyl-C-xyloside; 4-(looking yellow amide group) phenmethyl-C-glucuronide; 4-(looking yellow amide group) phenmethyl-C-glucoside; 4-(looking yellow amide group) phenmethyl-C-xyloside; and look yellow acyl group-beta-glucuronidase analogue; for example 1-(β-D-glucopyranose base) looks yellow acid amides and 1-(D-glucopyranose base alditol acyl group (uronosyl)) looks yellow acid amides; as United States Patent (USP) numbering 5516792; 5663377; 5599953; 5574177 and Bhatnagar etc.; Biochem.Pharmacol.; 41:1471-7 (1991) describes, and they are cited as a reference at this.Other fenretinide derivative can be considered to use in certain embodiments as those compounds of WO2006/063128 and WO2006/007314 description.WO2006/063128 and WO2006/007314 disclose other compound that can unite use with The compounds of this invention (for example, the compound of formula XI).WO2006/063128 and WO2006/007314 are quoted by complete as reference herein.
[0476] in certain embodiments, can accept experimenter's a kind of compound described herein that vitamin A derivatives comprises the disclosed compound of United States Patent (USP) numbering 4,743,400 (being cited as a reference at this), for example, the compound of formula XI.These retinoides comprise, and for example, that complete-anti--Wei A acyl chlorides, complete-anti--4-(methoxyphenyl) looks yellow acid amides (methoxyphenyl), 13-is suitable-and 4-(hydroxyphenyl) looks yellow acid amides and complete-anti--4-(phenelyl) looks yellow acid amides.Can consider to use United States Patent (USP) numbering 4 in certain embodiments, 310, the disclosed N-of 546 (being cited as a reference) (4-acyloxy phenyl)-complete-anti--look yellow acid amides, for example N-(4-acetoxyl group phenyl)-complete-anti--look yellow acid amides, N-(4-propionyloxy phenyl)-complete-anti--look yellow acid amides and N-(4-butyryl acyloxy phenyl)-complete-anti--look yellow acid amides at this.Can consider to use other vitamin A derivatives or meta-bolites in certain embodiments, for example N-(1H-tetrazolium-5-yl) look yellow acid amides, N-ethyl look yellow acid amides, 13-suitable-the N-ethyl looks yellow acid amides, N-butyl and looks yellow acid amides, Etretin (Etretin), etretinate, tretinoin (complete-anti--tretinoin) or isotretinoin (13-suitable-tretinoin).Referring to U.S. Provisional Patent Application numbering 60/582293 and 60/602675; Also visible Turton etc., M.J.Exp.Pathol., 73:551-63 (1992) all is cited herein as a reference.
[0477] in combination therapy, can give these compounds simultaneously, for example, with a kind of form of composition, or successive administration.When successive administration, the interval between twice administration can be one minute or several minutes, one hour or a few hours, one day or a couple of days, perhaps a week or several weeks.
[0478] treatment of one or more compounds described herein or the other therapies in preventive therapy and this area can be united use.For example, they can with operation and/or supplement, and/or radiation, and/or other methods of treatment is used in combination.Treatment to wet type AMD can be united use with the therapy of removing or destroy the neovascularity of outgrowth in spot.Laser, for example thermal laser can be used for this purpose.Transpupillary thermotherapy is a kind of selectable therapy, has wherein used infrared laser.Another kind method is a photodynamic therapy, can make the material of eyeball medium vessels to laser sensitization in this process medium sized vein injection, destroys abnormal vascular with laser beam then.Also can use the photocoagulation therapy.
[0479] treatment also can with give antioxidant and unite use, for example, high dosage antioxidant, for example (vitamins C, vitamin-E, β-Hu Luobusu), zinc and copper (" supplement therapy ").The antioxidant preparation comprises the combination of vitamins C, vitamin-E and β-Hu Luobusu.The daily dosage of the regulation of antioxidant and zinc is that about 500 milligrams of vitamins C, vitamin-E are that to be 15 milligrams, zinc count 80 milligrams, copper with zinc oxide counts 2 milligrams (adopting) with copper oxide in relevant eyeball disease of age (ARED) research for 400 international unit, β-Hu Luobusu.Many new drugs can prevent or delay photoreceptor cell death and retinal degeneration.These medicines comprise PKC412 (short neovascularity growth or chemical substance that blood vessel is taken place in the body capable of blocking), glial cell derived neurotrophic factor (a kind of survival factors, can delay the sex change in the rodent model), diatazem (a kind of calcium channel blocker, the rare retinene genetic flaw that can treat β-PDE by name).
[0480] the macular degeneration methods of treatment of describing as the present invention and radiotherapy are united when using, in this treatment preferably the width of cloth form of penetrating comprise: proton beam, Strontium-90, Pd 103, radiosurgery and EBRT (external beam radiotherapy).The methods of treatment of " wet type " macular degeneration is used to destroy blood vessel and stops neovascularization.After operation, carry out radiotherapy and can prevent or reduce cicatrization by the cell that kills or act on the cell of forming new vessel, epulotic inflammatory cell and formation fibrous tissue.
[0481] two kind of therapy can simultaneously or be carried out continuously.For example, at first take operative therapy, give the compound that one or more the present invention describe then.Perhaps, after the compound that gives one or more the present invention's descriptions, undergo surgery.Can before or after for example performing the operation, second kind of methods of treatment give the compound that one or more the present invention describe.
[0482] can use other therapies before or after this pharmacotherapy, the timed interval can be several minutes to a few days or several weeks.In the embodiment that other macula luteas or retinal degeneration therapy and this pharmacotherapy are used together, the timed interval between preferably avoiding treating each time is oversize.In these cases, we thought timed interval that the doctor gives two kinds of therapies about 12-24 hour, and more preferably from about 6-12 hour, be 12 hours most preferred time of lag.But in some cases, may need significant prolongation treatment time, be separated by a couple of days (2,3,4,5,6 or 7) or several weeks (1,2,3,4,5,6,7 or 8) between the treatment each time.
[0483] need prevent blind or retinal degeneration more than method and this pharmacotherapy of a kind of other treatment macula lutea or retinal degeneration as can be seen.Can use multiple combination treatment, wherein macula lutea or retinal degeneration therapy are " A ", therapy based on medicine is " B ", in the following example shown in: A/B/A B/A/B B/B/A A/A/B B/A/A A/B/B B/B/B/A B/B/A/BA/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/AB/A/A/B B/B/B/AA/A/A/B B/A/A/AA/B/A/AA/A/B/AA/B/B/B B/A/B/B B/B/A/B.
[00484] can use the physiology of one or more can accept the pharmaceutical composition that the preparation of carrier or auxiliary material is used according to present method according to traditional method.Therefore active compound and their physiology suitability salt or dissolved matter can be mixed with some can be by for example injecting, suck or be blown into the form of (by mouth or nose), oral, tongue or rectal administration and enterally administering.In one embodiment, (for example eye or retina) local this compound that uses at the position that has target cell (for example sick cell).
[0485] compound can be mixed with various dosages, comprises whole body and topical.Correlation technique and prescription are seen Remmington ' s Pharmaceutical Sciences, MeadePublishing Co., Easton, PA.With regard to the whole body administration, preferred drug administration by injection comprises intramuscular, intravenously, intraperitoneal and subcutaneous injection.With regard to injection, this compound can be mixed with liquor, preferred physiological compatibility damping fluid is hanks liquid or woods lattice (family name) solution for example.In addition, also this compound can be mixed with solid form, before use it be dissolved again or suspend.Also comprise the lyophilized form.
[0486] with regard to oral administration, the adoptable form of this pharmaceutical composition comprises according to traditional method uses pharmacy can accept auxiliary material for example for example tablet, lozenge or the capsule of tackiness agent (for example pregelatinized corn starch, polyvinylpyrrolidone or Vltra tears), weighting agent (for example lactose, Celluloasun Microcrystallisatum or secondary calcium phosphate), lubricant (for example Magnesium Stearate, talcum or silicon-dioxide), disintegrating agent (for example potato starch or primojel) or wetting agent (for example sodium lauryl sulphate) preparation.Can use method well known in the art with the tablet dressing.Oral liquid can use pharmacy can accept additive (for example sorbyl alcohol, derivatived cellulose, hydrogenation edible fat), emulsifying agent (for example Yelkin TTS or gum arabic), non-aqueous media (for example ationd oil, lipid, ethanol or refined vegetable oil) according to traditional method; Sanitas (for example methyl p-hydroxybenzoate or propyl ester, or Sorbic Acid).Said preparation also may comprise suitable buffering salt, perfume compound, tinting material and sweeting agent.Oral Preparation can suitably be mixed with the control-released agent of this active compound.
[0487] for inhalation, can easily this compound be stored in pressurized package or the atomizer use suitable propellent for example Refrigerant 12, trichlorofluoromethane, dichloro tetrafluoro ethane, carbonic acid gas or other suitable gas with the spray form administration.The dosage of pressurized spray agent can give quantitative medicine by valve and measure.Capsule that uses in sucker or the insufflation or gelatin cartridge case can be mixed with and contain for example form of lactose or starch of this compound powder mixture and a kind of suitable powder matrix.
[00488] this compound can be mixed with parenteral admin form, for example single injection or continuous infusion by injection.The injection preparation can be unit dosage form ampoule or be stored in the multi-dose container and add sanitas for example.This compound can be taked the solution of suspension, oil medium or aqueous medium or the form of emulsion, may comprise for example such preparation reagent of suspensoid, stablizer and/or dispersion agent.Perhaps, this active ingredient is taked powder type and is mixed for example sterile pyrogen-free water before use with appropriate carriers.
[0489] also this compound can be mixed with rectal administration form for example suppository or enema,retention, for example comprise conventional suppository bases such as theobroma oil or other glyceryl ester.
[0490] preparation except describing before also can be mixed with this compound a kind of prolonged action preparation.This prolonged action preparation can be by implanting (for example subcutaneous or intramuscular is implanted) or administered intramuscular.Therefore, can use many materials poly-or hydrophobic material (for example in oil applicatory, forming emulsion) or ion exchange resin in this compound formulation, or the derivative that is mixed with microsolubility slightly soluble salt for example.
[0491] compound described of one or more the present invention of pharmaceutical composition (comprising make-up composition) (for example 0.001 to 10% or from 0.1% to the 5%) mass percent that may contain 0.00001 to 100%.
[0492] in one embodiment, a kind of compound that the present invention is described is contained in a kind of topical formulations, and said preparation contains the topical carrier that generally is applicable to topical and comprises any this kind material known in the art.Form that appropriate carriers gives said composition expectation for example ointment, lotion, emulsifiable paste, microemulsion, gel, oil, solution or similar type can be selected for use, and a kind of natural or synthetic materials may be comprised.The preferred carrier that active medicine or other compositions of topical formulations do not had undesirable action.The suitable topical carrier that the present invention uses comprises for example water, alcohols and other avirulent organic reagents, glycerine, mineral oil, silicone, mineral jelly, hair fat, lipid acid, vegetables oil, parabens, wax and other analogues.
[0493] preparation can be ointment, lotion, emulsifiable paste, microemulsion and a gel colourless, that nothing is smelt.
[0494] compound can be contained in and be generally the semi-solid preparation form and matrix is generally in the ointment of Vaseline or other petroleum derivatives.Those skilled in the art concrete ointment base that uses in a road should be the matrix that can obtain best administering effect, and the matrix that other desired characteristic preferably can also be provided is tenderizer etc. for example.For other carriers or medium, a kind of matrix of ointment should be inert, stable, nonirritant and nonsensitized.As described in Remington, in content before, also be cited, ointment base can be divided into four classes: greasing base, emulsifiable base, emulsion matrix and water-soluble base.Greasing base comprises for example vegetables oil, Tallow, beef and is derived from the semi-solid hydrocarbon polymer of oil.Emulsifiable base also is known as the absorption ointment base, and not moisture or water-content seldom comprises for example hydroxystearin sulfate, lanolin anhydrous bp93 and hydrophilic petrolatum.Emulsion matrix is water-in-oil (W/O) or oil-in-water emulsion, comprises for example hexadecanol, glyceryl monostearate, lanolin and stearic acid.Water-soluble ointment base can be by polyoxyethylene glycol (PEGs) preparation of different molecular weight size; More information can be with reference to Remington ' s, and is the same.
[0495] compound can be contained in and be generally used for skin surface and do not produce in the lotion of friction, and this formulation is generally liquid or semi-solid preparation, and solid particulate wherein (comprising active ingredient) is present in water or the alcohols matrix.Lotion usually may comprise a kind of liquid oiliness emulsion of oil-in-water form for the solid suspension agent.So preferred lotion during owing to the easier application treatment of liquid composition big area body surface.Usually need be with the insoluble substance fine dispersion in the lotion.Lotion comprises with the suspensoid that produces better dispersion effect usually and active ingredient can be concentrated and keep it and the compound of skin contact, for example methylcellulose gum, Xylo-Mucine or analogue.The exemplary lotion preparation of uniting use with present method comprises by Beiersdorf, Inc. (Norwalk, Conn.) manufacturer of company product Aquaphor by name RTMHydrophilic petrolatum blended propylene glycol.
[0496] compound can be contained in the ointment that is generally thickness body fluid or semi-solid emulsion (oil-in-water or water-in-oil) form.Emulsifiable paste matrix be can wash and comprise a kind of oil phase, a kind of emulsifying agent and a kind of liquid phase.This oil phase contains Vaseline and Fatty Alcohol(C12-C14 and C12-C18) for example 16 or stearyl alcohol usually; The volume of liquid phase usually but not necessarily always greater than oil phase, often contain a kind of wetting Agent for Printing Inks.As described in above-mentioned Remington ' s, the emulsifying agent in the cream formulation often is nonionic, negatively charged ion, positively charged ion or amphoterics.
[0497] compound can be contained in the microemulsion, this formulation is, the unidirectional refraction clarifying dispersion agent stable to temperature variation that two kinds of immiscible fluids (for example oil and water) form, the interfacial film that surfactant molecule forms is with the two stable (Encyclopedia of PharmaceuticalTechnology (New York:Marcel Dekker, 1992), volume 9).In microemulsion, tensio-active agent (emulsifying agent), cosurfactant (co-emulsifier), a kind of oil phase and a kind of water are essential.Suitable tensio-active agent comprises any tensio-active agent that can be used for preparing emulsion, for example is usually used in preparing the emulsifying agent of emulsifiable paste.Cosurfactant (co-emulsifier) is selected from polymerization glycerol derivative, glycerol derivative and Fatty Alcohol(C12-C14 and C12-C18) usually.Preferred solvent/co-emulsifier makes up usually but might not be selected from glyceryl monostearate and polyoxyethylene stearic acid ester, polyoxyethylene glycol and polyoxyethylene glycol palmityl stearate, the acid of sheep ester and sheep ester acid glycerol three esters and oleoyl macrogolglycerides.Water comprises that not only water also generally includes damping fluid, glucose, propylene glycol, polyoxyethylene glycol, preferred end molecular weight polyisoprene ethylene glycol (for example PEG 300 and PEG 400) and/or glycerine and other analogues, and oil phase generally includes for example fatty acid ester, improvement vegetables oil, silicone oil, glycerine monoester, two fat and the mixture of three fat, monoester and two fat (for example oleoyl polyethylene glycol glycerol ester) of PEG.
[0498] compound can be contained in the gel preparation, this formulation is a semisolid systems, usually contain by being evenly distributed on the little inorganic particle (two-phase system) in the liquid vehicle (single-phase gels) or the semisolid of big organic granular and form, for example can be with active ingredient, a kind of carrier and a kind of suitable gelifying agent be tragakanta (concentration is 2 to 5%) for example, sodiun alginate (2-10%), gelatin (2-15%), methylcellulose gum (3-5%), Xylo-Mucine (2-5%), carbomer (concentration is 0.3 to 5%) or polyvinyl alcohol (concentration is 10 to 20%) mix until forming semi-solid product and prepare single-phase gels.Other suitable gelifying agents comprise Walocel MT 20.000PV, polyoxyethylene-polyoxypropylene, Natvosol and gelatin.Though use gel as the water carrier fluid usually, alcohols and oils also can be used as carrier fluid.
[0499] also can comprise various additive well known to those skilled in the art in the preparation (for example local application's preparation).Example additives includes, but are not limited to solubilizing agent, skin absorption promoter, opalizer, sanitas (for example antioxidant), jelling agent, buffer reagent, tensio-active agent (especially nonionic and amphoterics), emulsifying agent, tenderizer, thickening material, stablizer, wetting agent, tinting material, perfume compound and analogue.Especially preferably comprise solubilizing agent and/or skin absorption promoter, comprise emulsifying agent, tenderizer and sanitas simultaneously.A kind of optimal partial preparation comprises about 2wt.%-60wt.%, solubilizing agent and/or the skin absorption promoter of preferred 2wt.%-50wt.%; 2wt.%-50wt.%, the emulsifying agent of preferred 2wt.%-20wt.%; The sanitas of 2wt.%-20wt.% tenderizer and 0.01-0.2wt.%, active substance and carrier (for example water) constitute the remainder of said preparation.
[0500] skin absorption promoter is used for the not injured skin of the active medicine of assisting therapy amount through the fair-sized zone.Suitable promotor known in the art comprises: lower alcohol is methyl alcohol, ethanol and 2-propyl alcohol for example; The alkyl methyl sulfoxide is dimethyl sulfoxide (DMSO) (DMSO), Decylmethyl Sulphoxide (C10MSO) and ten tetramethyl-sulfoxides for example; Pyrrolidone is 2-Pyrrolidone, N-N-methyl-2-2-pyrrolidone N-and N-(hydroxyethyl) pyrrolidone for example; Urea; N, the N-diethyl--methyl benzamide; C2-C6 alkane glycol; Other solvent such as N, dinethylformamide (DMA), N, the azepan of N-N,N-DIMETHYLACETAMIDE (DMA) and tetrahydrofurfuryl carbinol and 1 replacement-2-ketone, especially 1-just-dodecane basic ring azepan-2-ketone (1-n-dodecylcyclazacycloheptan-2-one) (laurocapram, can be available from WhitbyResearch Incorporated, Richmond, Va, commodity are called AzoneR TM).The example of solubilizing agent includes, but are not limited to following material: hydrophilic ether is diethylene glycol monoethyl ether (oxyethyl group Diethylene Glycol, commodity are called TranscutolRTM) for example; (commodity are called Softcutol to Diethylene Glycol list oleyl ether RTM); The polyethylene castor oil derivative is polyoxy 35 Viscotrol C, polyoxy 40 hydrogenated castor wet goods for example; Polyoxyethylene glycol is low molecular poly PEG 300 and PEG 400 and polyethyleneglycol derivative PEG-8 caprylic acid/capric acid glyceryl ester (commodity are called LabrasolRTM) for example for example especially; The alkane methyl sulfoxide is DMSO for example; Pyrrolidone is 2-Pyrrolidone, N-N-methyl-2-2-pyrrolidone N-and DMA for example.Many solubilizing agent also can be used as absorption enhancer.Can in preparation, comprise a kind of solubilizing agent or comprise the mixture of multiple solubilizing agent.
[0501] suitable emulsifying agent and co-emulsifier include, but are not limited to emulsifying agent and the co-emulsifier described in the relevant microemulsion formulation.Tenderizer comprises for example propylene glycol, glycerine, isopropyl myristate, polypropylene glycol-2 (PPG-2), myristate propionic salt and analogue.
[0502] also can comprise other active ingredient for example other antiphlogiston, anodyne, antimicrobial drug, antifungal drug, microbiotic, VITAMIN, antioxidant and be present in sunscreen in the sunscreen formulations usually in the preparation, include, but are not limited to anthranilic acid, benzophenone (especially 3-benzophenone), camphor derivatives, cinnamate (for example Uvinul MC-80), DBM (for example butyl methoxy DBM), vitamin Bx (PABA) and derivative and salicylate (for example octyl salicylate).
[0503] in certain embodiments, the amount of this active ingredient accounts for the 0.25wt.%-75wt.% of said preparation, preferably about 0.25wt.%-30wt.%, more preferably from about 0.5wt.%-15wt.%, most preferably from about 1.0wt.%-10wt.%.
[0504] the topical skin treating composition can be packaged in the proper container and use with the expection that adapts to its viscosity and human consumer.For example, lotion and emulsifiable paste can be packaged in bottle or the ball medicator, or in the sprays that is driven by propellent, or have assembled in the container of pump of suitable finger manipulation.When composition can be stored in indeformable bottle or the squeeze receptacle during for emulsifiable paste, pipe or have in the bottle of lid in for example.Said composition also can be included in the capsule, United States Patent (USP) .5 for example, the capsule of describing in 063,507.Accordingly, the present invention also provides the container that seals of the cosmetics-stage composition that holds the present invention definition.
[0505] in a selectable embodiment, provide a kind of can be oral or the pharmaceutical preparation of enterally administering, said preparation may comprise aforesaid a kind of microemulsion that contains active compound, but may contain other pharmaceutical acceptable carrier of being particularly useful for oral or enterally administering, medium, additive etc.Perhaps do not make the form that microemulsion that any change will contain active compound according to aforesaid method is mixed with oral or enterally administering.
[0506] can be according to the method afford cell that gives the experimenter graft (for example a kind of compound of usefulness of describing of the present invention in vitro handled cell), this method may with give a kind of immunosuppressor for example Ciclosporin A unite use.The W.Sheridan eds of " cell therapy: stem cell transplantation, gene therapy and cellular immunization therapy Cell Therapy:Stem CellTransplantation can write with reference to G.Morstyn and to(for) the ultimate principle reader of pharmaceutical preparation, Gene Therapy, Cellular Immunotherapy ", the Cambridge University Press, 1996 and E.D.Ball, the HematopoieticStem Cell Therapy that J.Lister and P.Law write, Churchill Livingstone, 2000.
[0507] the present invention also provides the cover box, the cover box that for example is used for the treatment of or diagnoses.The cover box may comprise the compound and the apparatus that tissue or cell are contacted with this compound that one or more the present invention describe.This apparatus comprises that needle, syringe, support, resuspended liquid and other can introduce the intravital apparatus of experimenter with a kind of compound.
[0508] to get rid of 1 especially in described any one embodiment before, two (the p-aminophenyl oxygen base) pentanes of 5-.
[0509] to get rid of 11-cis-Vogan-Neu especially in described any one embodiment before.
[0510] to get rid of 11-cis-Vogan-Neu palmitate especially in described any one embodiment before.
[0511] to get rid of 13-cis-vitamin A acid (accutane) especially in described any one embodiment before.
[0512] to get rid of 2-bromine hexadecanoic acid especially in described any one embodiment before.
[0513] to get rid of 3-subcutin mesylate especially in described any one embodiment before.
[0514] to get rid of paracetamol especially in described any one embodiment before.
[0515] to get rid of amantadine especially in described any one embodiment before.
[0516] to get rid of all-trans-retinal especially in described any one embodiment before.
[0517] to get rid of all-trans-retinoic acid especially in described any one embodiment before.
[0518] to get rid of alltrans retinol (vitamin A) especially in described any one embodiment before.
[0519] to get rid of the alltrans retinol cetylate especially in described any one embodiment before.
[0520] to get rid of aniline especially in described any one embodiment before.
[0521] to get rid of hexahydroaniline especially in described any one embodiment before.
[0522] to get rid of dapsone especially in described any one embodiment before.
[0523] to get rid of diaminobenzene oxygen pentane especially in described any one embodiment before.
[0524] to get rid of the gavaculine ethyl ester especially in described any one embodiment before
[0525] to get rid of the m-anthranilic acid ester especially in described any one embodiment before.
[0526] in any one embodiment before, to get rid of especially between-phenetidine.
[0527] in described any one embodiment before, to get rid of N-(4-hydroxyphenyl) especially and look yellow acid amides (fenretinide).
[0528] to get rid of N, accelerine especially in described any one embodiment before.
[0529] to get rid of N especially, N-dimethyl-p-phenetidine in described any one embodiment before.
[0530] to get rid of methylphenylamine especially in described any one embodiment before.
[0531] to get rid of N-methyl-p-phenetidine especially in described any one embodiment before.
[0532] to get rid of neighbour-phenetidine especially in described any one embodiment before.
[0533] in described any one embodiment before, to get rid of neighbour-(just-hexyloxy) aniline especially.
[0534] in described any one embodiment before, to get rid of right-(just-hexyloxy) benzamide especially.
[0535] in described any one embodiment before, to get rid of right-(just-hexyloxy) benzoyl hydrazine especially.
[0536] to get rid of right-anisidine especially in described any one embodiment before.
[0537] to get rid of right-ethylaniline especially in described any one embodiment before.
[0538] to get rid of right-phenetole methylamine especially in described any one embodiment before.
[0539] to get rid of right-thanatol especially in described any one embodiment before.
[0540] to get rid of phenetidine especially in described any one embodiment before.
[0541] to get rid of piperidines especially in described any one embodiment before.
[0542] in described any one embodiment before, to get rid of especially right-just-butoxy aniline.
[0543] in described any one embodiment before, to get rid of especially right-just-butylaniline.
[0544] in described any one embodiment before, to get rid of especially right-just-dodecyl polyaniline.
[0545] to get rid of p-Nitraniline especially in described any one embodiment before.
[0546] to get rid of Sulfabenzide especially in described any one embodiment before.
[0547] in any one embodiment before, to get rid of sulfamoxole (sulfamoxaole) especially.
[0548] to get rid of sulfanilamide (SN) especially in described any one embodiment before.
[0549] to get rid of tricaine especially in described any one embodiment before.
[0550] in addition, any embodiment before any compound in the incorporated by reference document of the present invention also may be excluded in.
[0551] 4. method
[0552] the invention discloses the method for the treatment of or preventing a kind of ophthalmic diseases.Illustrative methods comprises the composition a kind of pharmaceutical composition described of the present invention for example that gives a kind of therapeutic dose of experimenter's (for example needing to accept the experimenter of this treatment).The experimenter that need accept this pharmacological agent knows oneself to have suffered from or developed into probably the experimenter of ophthalmic diseases.
[0553] as mentioned above, can give a kind of disclosed composition of experimenter with treatment or prevention macular degeneration.Other is relevant poison retina compound for example lipofuscin disease, disorder or the state of an illness of in retinal pigment epithelium, piling up also can treat (for example lipofuscin cause retinopathy) by similar method.
[0554] method described of the present invention can be used for treating or prevents any type of and the relevant macular degeneration of lipofuscin accumulation, for example heredity or degeneration macula lutea disease, for example relevant with age macula lutea degenerative change (AMD).Two kinds of macula lutea degenerative changes relevant with the age are arranged, dry (atrophic type) and wet type (new vessel type or exudative type) macular degeneration.
[0555] as mentioned above, macular degeneration (also being known as retinal degeneration) is a kind of eye disease that relates to the macular degeneration of retina middle portion.The macular degeneration of about 85%-90% is drying type (atrophic type or do not have the new vessel type).
[0556] in the drying type macular degeneration, the formation of retinal degeneration and little yellow settling (being called the little wart of retina) is relevant.This phenomenon causes spot attenuation and dehydration.The site and the quantity of the retina attenuation that is caused by druse are directly related with the forfeiture of central vision.Layer of retina,pigmentary sex change and the photosensory cell atrophy that is covered in the little wart of retina cause slowing down of central vision.This process usually occurred in 10 years or in longer time.Experimenter with serious figure shape atrophy can blind very soon.The method that can use the present invention to describe is treated these experimenters.
[0557] manyly causes that by the age related macular degeneration people of visual deprivation suffers from the wet type macular degeneration.In the wet type macular degeneration, come from the choroidal improper blood vessel of eyes (being known as new vessel formation under the retina) and under retina and macula lutea, grow.Fibrous tissue constantly be bred and be contained to these blood vessels will, at macula lutea bleed bottom and liquid body exudate, make the macula lutea bulging or move and twist central vision.When transudate or hemorrhagely be deposited in the retina or acute visual deprivation will appear in retina following time.Permanent visual deprivation will take place when outside retina begins atrophy or replaced by fibrous tissue.
[0558] Si Tajiateshi disease (STGD) is a kind of degeneration form of macular degeneration, is fallen ill in the Childhood.The Clinical symptoms of STGD comprises central vision carrying out property forfeiture and is covered in retinal pigment epithelium (RPE) progressive atrophoderma on the macula lutea.The encode ABCR genovariation of RmP of people causes STGD.It is slow to reveal dark adatpation in the early stage patient table of disease, but the staff cell function is normal.Saying that from histology STGD is relevant with the deposition of lipofuscin particle in the RPE cell, is to digest impaired causing afterwards by engulfing the far-end acromere (shed distalouter-segments) that comes off by inference.Cause the RPE sex change afterwards, the photosensory cell sex change occurs in the disease later stage.Can draw following inference: STGD from this lysis causes by RPE is damaged.But, must observe the pattern that early stage RmP only appears at acromere and do not express RPE sex change and the maintenance (preservation) that just can determine photosensory cell in the RPE cell.
[0559] some AMDs are owing to genovariation causes, for example gene A BCA4, ELOVL4, PROML1, VMD2, Peripherin/RDS, EFEMP1, TIMP3 and XLRS1.A kind of G196IE that sports of ABC4A gene.Macular dystrophy also comprises following disease: Stargardt disease/yellow point-like eyeground (OMIM 248200), and this is a kind of autosomal recessive disease, characteristics are that a sudden change takes place chromogene seat Ip21-p22 (STGD1); Class Stargardt macular dystrophy (OMIM 600110) is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 6q14 (STGD3); Class Stargardt macular dystrophy (OMIM 603786) is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 4p (STGD4); Autosomal dominant " bulU ' s eye " macular dystrophy is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 4p (MCDR2); Best macular dystrophy (OMIM153700) is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 1Iq13; Adult's vitelliform dystrophy (OMIM 179605) is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 6p21.2-cen; Malnutritive pattern (OMIM 169150) is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 6p21.2-cen; Doyne honeycomb retina malnutrition (OMIM 126600) is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 2p16; North Carolina macular dystrophy (OMIM 136550) is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 6q14-q16.2 (MCDR1); The autosomal dominant macular dystrophy that is similar to MCDR1 is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 5p15.33-p13.1 (MCDR3); Class North Carolina macular dystrophy is with deaf relevant, and it is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 14p (MCDR4); Carrying out property biforcal atrophia choroideae et retinae (OMIM 600790) is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 6q14-q16.2; Sorby ' s fundus dystrophy (OMIM 136900) is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 22q12.1-q13.2; Centrality halo shape choroid malnutrition (OMEVI 215500) is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 6p21.2-cen17p13; Dominance cryptomere macular dystrophy (OMEVI 153880) is a kind of autosome dominant disease, and characteristics are that a sudden change takes place chromogene seat 7p15-p21; Teenager's retinoschisis (OMIM 312700) is a kind of X-linkage disease, characteristics be chromogene seat Xp22.2 take place a sudden change (Michaelides etc. (2003) J.Med.Geneet.40:641).The method that the present invention describes can be used for treatment or prevents any type of gene genetic macular dystrophy, as long as these diseases are relevant with the sick similar and abnormal lipofuscin accumulation of Stargardt with AMD.
[0560] other disease that can treat or prevent comprises cone cell-staff cell malnutrition, the retinitis pigmentosa of some type and yellow point-like eyeground.
[0561] in one embodiment, a kind of medicine is given the experimenter will occur in a certain step short circuit of the visual cycle in the staff cell membranous disc.For example as shown in Figure 3, this medicine may act on the 11-cis-retinene among the RPE and make it branch to the retinene that is all-trans when it is retained among the RPE.More definite says, this medicine may and form a kind of intermediate that can be isomerizated into the alltrans configuration with 11-cis-retinene effect.This alltrans intermediate may discharge this medicine to form alltrans-retinene.This alltrans-retinene is processed (identical with the normal processes among the RPE) again in remaining visual cycle then.Therefore, visual cycle is reduced to invalid circulation, and wherein all-trans-retinal seldom or have no chance to build up in membranous disc.
[0562] in one embodiment, the experimenter may be suffered from macular degeneration by diagnosis, gives its a kind of disclosed medicine or conjoint therapy then.In another embodiment, the experimenter may be diagnosed with and may develop into macular degeneration (the risk level factor comprises smoking history, age, women and family history).In another embodiment, the experimenter may be suffered from this disease by diagnosis before tangible retinal damage occurring.For example, find that patient carries the transgenation of α bcr, elovl4 and/or other gene and therefore suffered from recessive macular dystrophy by diagnosis before showing any ophthalmology sign, find that perhaps the experimenter early stage macula lutea occurs and changes, these change recognizes the experimenter and to have indicated before eyesight is affected macular degeneration may take place.In some embodiments, the experimenter knows that it need treat or prevent macular degeneration.
[0563] doctor can come diagnose macular degeneration by using ophthalmofundoscope or slit lamp examination eyes usually.Sometimes use FA (in this process doctor in vein, inject dyestuff and to retina film making) to determine diagnosis.Autofluorescence develops and light-gathering scan laser ophthalmofundoscope can detect the lipofuscin accumulation.
[0564] monitors experimenter's macular degeneration degree in some embodiments.The method that multiple monitoring experimenter is arranged, for example examination of eyes, eye expansion inspection, fundoscopy, visual acuity test, vasography, FA and/or examination of living tissue.Detection can be carried out at various time points.For example monitoring after giving medicine.Carry out once in detection can be after the administration first time a day, a week, two weeks, one month, two months, six months, 1 year, 2 years and/or 5 years.Can monitor patient repeatedly.In certain embodiments, can change drug dose according to the monitoring situation.
[0565] in some embodiments, the disclosure method can be united use with the method for other treatment or prevention macular degeneration, for example photodynamic therapy.The present invention has also described other method.
[0566] in some embodiments, be used for the treatment of or prevent the medicine of macular degeneration can life-time service.The administration frequency of this medicine can be for once a day, greater than once a day, twice weekly, on every Wendesdays time, once in a week, biweekly, every month once, bimonthly, half a year once, once a year and/or once every two years.
[0567] can give this medicine by number of ways described above.In some embodiments, can pass through tablet, capsule, liquid, paste and/or powder type oral administration.In some embodiments, can be by for example intraocular injection topical.In some embodiments, this medicine can be activated by embedding (caged), covering form or other inactive form whole body administration and at eye (for example motivation therapy).In some embodiments,, can make this medicine slowly-releasing in for some time like this, for example in a few hours, a few days, several weeks and/or several months with bank (depo) form administration.
[0568] usage quantity of this medicine alters a great deal for the treatment significant quantity and according to employed certain drug.The dose that comprises in the composition also depends on the time that drug level that needed release profiles, a kind of biological effect require and this biologically active drug need discharge when being used for the treatment of.This biologically active substance can mix with a kind of matrix with different loading amount concentration in a certain embodiment, only need at room temperature carry out and not need organic reagent in one embodiment.In other embodiments, said composition can be mixed with microballoon.In some embodiments, this medicine can be mixed with sustained release preparation.
[0569] should be noted that by disturbing the visual cycle to stop A 2(half-light) eyesight at night that the accumulation of E may damage patient also may cause nyctalopia.The present invention describe some be considered to be applicable to and prevent A 2The medicine that E builds up is used or not exclusively uses by conservative always really, and this is because they have the tendency that causes nyctalopia.But, recognize that this causes that the nyctalopia inducement may influence and treats and/or prevents macular degeneration, need the patient of this treatment to be ready to accept slight nyctalopia probably as obtaining the insufficient cost of twenty-twenty vision.This is that this mechanism only exists under half-light because the visual cycle described above is present in the shaft-like photosensory cell, and do not exist daytime.Therefore the visual cycle reduces very for a short time to the influence of macula lutea function, and Jue Dabufen people is ready to sacrifice some night visions and finally loses the possibility of cone cell eyesight on daytime to reduce them probably.
[0570] 5. screening method
[0571] can identify suitable medicine by a lot of screening methods.For example a kind of drug candidate can be suffered from the experimenter that maybe may suffer from macular degeneration, for example the animal of macular degeneration animal model is measured for example A of retinal toxicity compound then 2The accumulation of E.Compare the medicine that can reduce the retinal toxicity build up of compounds with contrast (not containing medicine) and can therefore be accredited as active drug.Another kind method is to analyze in the sight sensor dish whether have alltrans-Vogan-Neu, N-retinene-PE and/or A 2E.Macular degeneration develops rapidly that animal model has very big meaning, because macular degeneration generally needs time of several years under the native state.Many animal models can be used as the model of macular degeneration.For example as the elovl4-I-knock-out mice, α bcr-I-knock-out mice also is described to the model of macular degeneration and/or lipofuscin accumulation.The knock out mice of monocyte chemistry trend albumen-1 (Ccl-2 is also referred to as MCP-I) or its isoreceptor, C-C Chemokine Receptors-2 (Ccr-2) defective also can be used as the macular degeneration acceleration model in addition.
[0572] in addition, but the external model assisting sifting of vision system can suppress or the medicine of short circuit visual cycle.Can produce external model with suitable enzyme and other necessary cofactor incubation by the intermediate solution that will filter out.Perhaps can use external RPE culture system.For example can be by drug candidate being added in the solution that contains LRAT and a kind of LRAT substrate and measuring and expect that the amount of product detects the LRAT inhibition.Similarly system can be used for the detection of other potential target spot of the present invention's description.
[0573] can identify that also small molecules for example can suppress a kind of enzyme or the medicine of short circuit visual cycle in the visual cycle like this.For example identify can with a kind of bonded medicine in these enzymes.Screening experiment may comprise whether an a kind of enzyme and a medicine to be measured are contacted and detect this medicine can combine with this enzyme.Also can use a kind of bioactive fragment of enzyme.This enzyme or fragment label for example can be used fluorophor.Screening experiment also may be included under the condition that medicine to be measured exists a kind of enzyme is contacted with its substrate.These experimental techniques are also tested applicable to high flux screening.
[0574] screening experiment also can identify and can suppress the small-molecule drug that vitamin A transmits to eyes.A kind of method may be included under the condition that vitamin A exists the binding capacity that RBP and a kind of medicine to be measured is contacted and measure the RBP of vitamin A and existence when not having medicine.Another kind method may be included in the external eye model RPB is contacted with a kind of medicine to be measured, compares the amount of the vitamin A that is transported to eye model when adding vitamin A and mensuration and not having medicine.Other screening experiment may be included under the condition that vitamin A exists and to contact and to measure RBP and a kind of RBP acceptor when comparing when not having medicine to be measured and the amount of the RBP of RBP receptors bind.
Embodiment
[0575] use following examples further to illustrate the present invention, but that these embodiment do not have is any type of restricted.Content in institute's incorporated by reference document (comprise bibliographic reference that the application quotes everywhere, authorize change patent application sharp, that announced) clearly be contained among the present invention with the reference form.
[0576] embodiment 1:TDT and TDH combine with the mRPE65 high-affinity
[0577] material: available from W.L.Lawson Co., Lincoln, the freezing buphthalmos cup (eye-cups) of the collyriculum of retina of NE.Ethylenediamine tetraacetic acid (EDTA) (EDTA), phenyl-agarose CL-4B and Trizma
Figure A20068003723301081
Base, trans-trans-farnesol, pyridinium chlorochromate, Dess-Martin reagent, decyl magnesium bromide, cetylamine and dimethyl sulfoxide (DMSO) are all available from Sigma-Aldrich.Dithiothreitol (DTT) (DTT) is available from ICN Biomedi cals Inc.Anagrade TMCHAPS is available from Anatrace.The chromatographically pure solvent is available from Sigma-Aldrich Chemical s.Anti-RPE65 (NFITKVNPETLETIK) antibody is available from Genmed Inc.Wide spectrum does not have EDTA proteinase inhibitor cocktail agent available from Roche Biosciences.Precast gel (4-20%) is available from Amersham Biosciences.All reagent are analytical pure unless otherwise indicated.
[0578] method
[0579] experimentation on animals: experimental program is by state-run protection of animal of protection of animal standing committee of Harvard Medical School and Columbia University and the approval of the use council and follow vision and the guilding principle of ophthalmology research association formulation.7 weeks big male Balb/c small white mouses and big male these pula-Dao of 7 weeks come (family name) rats available from Charles River Breeding Laboratories, and be 12: raise under the condition of 12h in ratio round the clock.Produce big Abcr null mutation mouse (129/SV X C57BL/6J) of 8-10 week with the method for describing before (12,20), the light in circulation illumination in 12 hours and cage is to raise Abcr under the condition of 30-50lux -/-And Abcr + /+Mouse.At Abcr -/-And Abcr + /+In the mouse, by reported method before to Rpe65 check order [20].
[0580] purifying mRPE65: the method for describing before using from the buphthalmos cup [29] is extracted and purifying mRPE65.(1: 4,000 one anti-, following 1 hour of room temperature with argentation and Western blotting; 1: 4,000 two is anti-, following 0.5 hour of room temperature) the mensuration purity of protein.At slide-a-lyser available from Pierce TM(10KDa MWCO) dialyses exchange buffering liquid with desired damping fluid in the microdialysis card.Use Amicon Ultra available from Millipore Corp TMCentrifugal filter device (molecule 30KDa dams) concentrates RPE65 solution.Final protein soln contains 100mM pH7.4 phosphoric acid buffer salt solution (150mM NaCl) and 1%CHAPSO.Use Bio-Rad D CProtein determination kit is measured protein concentration according to improved sieve protein matter quantitative method [30].
[0581] synthetic:
[0582] 13,17,21-trimethylammonium-22 carbon-12,16,20-triolefin-11-ketone (TDT):Will be anti-, anti--farnesal (200mg, ether 0.9mmol) (2mL) solution in 0 ℃ add in the decyl bromination magnesium solution (the 1M diethyl ether solution, 1.5mL) and stirred 15 minutes.Then this reaction system is heated to room temperature, adds saturated NH again 4The Cl aqueous solution (1mL).Add H 2O (2mL) uses hexane (3x 5mL) to extract this reaction system then.The extract that merges is collected, used the salt water washing, with dried over mgso and reduction vaporization.Residue is carried out stratographic analysis (SiO 2, EtOAc-sherwood oil, 10: 90) and obtain alcohol (319mg, 92%); R f(EtOAc-sherwood oil, 2: 8) 0.56.CH to above-mentioned alcohol 2Cl 2(1.5mL) under room temperature, add in the solution Dess-Martin periodic acid lactone (periodinate) (419mg, 0.99mmol) and stirred 10 minutes.Use Sulfothiorine-sodium hydrogen carbonate solution (10% Sulfothiorine and saturated NaHCO then 3Aqueous solution volume ratio 1: 1 3mL) is handled this reaction system and lasting the stirring 10 minutes.Add H 2O (2mL), (3x 5mL) extracts this reaction system with hexane, uses the salt water washing, with the extract of dried over mgso and reduction vaporization merging.Residue is carried out stratographic analysis (SiO 2, EtOAc-sherwood oil, 1: 99) and obtain ketone (TDT) (283mg, 89%); R f(EtOAc-sherwood oil, 2: 8) 0.8; δ H (200MHZ; CDCl 3) 6.04 (and s, 1H), 5.19-5.01 (m, 2H), 2.44-2.30 (m, 2H), 2.20-1.85 (m, 8H), 1.71 (s, 3H), 1.59 (s, 6H), 1.55 (s, 3H) and 1.38-1.17 (m, 21H); M/z (ESI) (measured value: M+Na 383.3277, C 25H 44O requires M+Na383.3284).
[0583] 3,7,11-trimethylammonium-22 carbon-2,6,10-trienic acid palmitoyl amine (TDH): at room temperature to instead-anti--(100mg adds NaCN (31mg) and MnO in hexane 0.45mmol) (3mL) solution to farnesol while stirring 2(590mg), add then hexadecylamine (545mg, 2.2mmol) and stirred 1 hour.And then add a part of MnO 2(590mg) this mixture is stirred under room temperature spend the night then.Use silicon-dioxide and diatomite (celite) pad to filter this mixture and for several times then with hexane wash.Carry out stratographic analysis (SiO with the extract evaporation of merging and to residue 2, EtOAc-sherwood oil, 3: 97) and obtain 3,7,11-trimethylammonium-22 carbon-2,6,10-trienic acid Palmitoyl amine(145mg, 70%); R f(EtOAc-sherwood oil, 2: 8) 0.52; δ H (200MHZ; CDCl 3) 8.18 (d, J=9Hz, IH), 6.0 (d, J=9.6Hz, 1H), 5.2-5.0 (m, 2H), 3.42 (t, J=6.8Hz, 2H), 2.23-1.91 (m, 8H), 1.67 (s, 3H), 1.59 (s, 9H), 1.39-1.20 (m, 31H); M/z (ESI) (measured value: M+Na 482.4334, C 31H 57ON requires M+Na 482.2332).
[0584] fluorescence is in conjunction with mensuration: use the RPE65PBS solution of pH 7.4 in fluorometric titration is analyzed, contain 1%CHAPS.All titration are all carried out at 25 ℃.Excite the sample in the PSB damping fluid at the 280nm place, at 300 to 500nm scope interscan fluorescence.Use the right angle detection method in 25 ℃ of mensuration fluorescence on Jobin Yvon instrument Fluoromax 2, use the quartz colorimetric utensil of 450 μ L, light path is 0.5cm.
[0585] this instrument is measured the fluorescence of protein solution after 10 minutes 25 ℃ of balances.Then with the retinoid solution that is dissolved in DMSO under the condition that does not have top light this sample of titration and before fluorometric assay with the complete mixing of this solution.During titration each time, in the protein soln of 350 μ L, add the equivalent part, be generally 0.3 μ L.Fully make its balance carry out fluorescent strength determining in 10 minutes again after the mixing.Add DMSO (each titration 0.1%) to fluorescence intensity without any influence.According to aforementioned (17,19) fluorescence intensity calculations incorporated constants (KD).
[0586] Pharmacological agent and retinoid extraction:With DMSO as carrier with described medicine peritoneal injection.Control group is only injected DMSO.The injected in mice volume is that 50 μ L rats are 180 μ L.After the injection, these animals are raised under dark condition bleached then in 2 hours 2 hours.Eyeball is put to death and extractd in animal dark adatpation (mouse 5 minutes, rat 30 minutes) back.In experiment, use male Balb/c mouse and male this pula-Dao to come (family name) rat.
[0587] eyeball is placed 0.8mL 1M azanol/0.1M MOPS[3-(N-morpholino) propanesulfonic acid of pH 6.5] and 0.2%SDS and homogenate in the glass-glass homogenizer.Add ethanol (0.6mL) and at room temperature with homogenate incubation 30 minutes to form 11-cis-retinene oxime [31].With methylene dichloride (3x 0.4mL) extraction retinoid.The extract that merges with dried over mgso then, dry and analyze in argon gas stream with HPLC.Used positive HPLC post is YMC-PVA SIL NP, 250x 4.6mm, and moving phase is that (93: 7v/v), flow velocity is 1.5mL/min to hexane-dioxs.Measure absorption at the 325nm place, compare the judgement absorption peak with standard substance.In shown HPLC curve, measure retinyl ester and 11-cis retinene cis (syn)-oxime.The mouse recovery time is 5 minutes, and rat is 10 minutes.Regeneration rate and drug effect between Balbc/ mouse and pigment wt (the 129/SV X C57BL/6J) mouse (identical with the genetic background of Abcr knock-out mice) do not have difference.
[0588] Retinal current is measured (ERG):Before all ERG experiments, the mouse dark adatpation is spent the night.To study the acute effect of compound in order measuring, measure before be exposed to bleaching light before to make its in the dark stop one hour being dissolved in the 50mg/kg compound of 25uL DMSO under the dark red lamp under the mouse single film injection and carrying out ERG more.Give the DMSO of contrast (" being untreated ") animal injection 25uL.With mouse anesthesia and with 1% phenylephrine and 1% cyclopentolate expansion skew pupils, under 5000lux bleaching light, expose 2 minutes with ketamine (80mg/kg) then.
[0589] in about 50 minutes after bleaching finishes from cornea that cotton core physiological saline electrode is connected write down ERG.Subcutaneous No. 30 pins of forehead and trunk are respectively as reference and ground-electrode.Animal is placed on the well heater can keeps its body temperature at 37 ℃.Light stimulus comes from the Ganzfeld stimulator with stroboscope, and (PS33Grass Instruments Inc., WestWarwick RI), will change instrument took out and placed mouse head from cover top and rear.To glisten diffusion evenly to block this stimulator.With one indicate graduated photometer measurement flash intensity (J 16 Tektronics Instruments, Beaverton, OR).With the data acquisition system of Macintosh computer control with the frequency of 0.1Hz with responded average (PowerLab, ADInstruments, Mountain View, CA).
[0590] after 3 days identical animal being carried out ERG according to identical experimental program (except not injecting (repetition) compound) tests.
[0591] TissueExtraction Analyze with HPLC:Collect back eyecup and using-system grind device in PBS with its homogenized.Add the chloroform/methanol mixture (2: 1) of equal volume and with this mixture extraction 3 times.Filter extract and make it contain 0.1%TFA methanol solution anti-phase that (C18Sep-Pak, Millipore) cartridge is to remove insoluble substance through one with cotton.Gas evaporation down is dissolved in extract in the methyl alcohol that contains 0.1%TFA except that after desolvating.Use Waters Alliance 2695HPLC, Atlantis
Figure A20068003723301121
DC18 post (Waters, 4.6x150mm, 3 μ m) and gradient acetonitrile solution (containing 0.1% trifluoroacetic acid): 90-100% (0-10min), 100% acetonitrile (10-20min) is to detect at the 430nm place under the condition of 0.8mL/min to absorb quantitative A at flow velocity 2E.Sample size is 10 μ L.Under dark red light, extract with HPLC sample introduction.By the pure A of reference external standard HPLC- 2E/ is different-A 2The quantitative A of E 2E/ is different-A 2The concentration of E.Because A 2E/ is different-A 2E can reach photo-equilibrium in vivo, so term A unless otherwise indicated 2E refers to two kinds of isomer.
[0592] The result
[0593] The design of specificity mRPE65 antagonist and activity in vivo thereof:Show that mRPE65 saturability ground combines K with alltrans retinyl-cetylate (tRP) in the quantitative fluorescence research before D=47nM[17,19].Part combines to such an extent that structure-activity research shows that the acid amides of tRP and ketone Equivalent and tRP itself have similar binding ability [data are unexposed] with mRPE65.And isoprenoid, for example the C15 farnesyl can replace alltrans retinyl-part [data are unexposed].Based on these observationss, we have prepared instead, and anti--farnesylation ketone (TDT) and acid amides (TDH) is shown in Fig. 4 A-B.MRPE65 shows that with the fluorometric titration of TDT and TDH but TDT and TDH specificity combine ox mRPE65 among Fig. 4 A-B.Excitation wavelength is 280nm, passes the solution layer of 0.5cm and observes emission light.Volumetric soiutions comprises 0.952 μ MmRPE65 and 1%CHAPS of the 100nM phosphate buffered saline (PBS) (150mM NaCl) that is dissolved in pH 7.4.Picture group among Fig. 4 A (a) has shown the emissioning light spectrum of mRPE65 when combining with TDT.Picture group (b) has shown the variation along with the increase 338nm place fluorescence intensity of TDT and TDH concentration.Picture group (c) has shown that the linearity two of Po α vs Ro α/(1-α) equation of mRPE65 titration TDT or TDH takes advantage of matched curve [17,19].TDT bonded K D=58 ± 5nM and TDH bonded K D=96 ± 14nM.These experiments are foundation with the following fact: the specific combination of these analogues and mRPE65 can cancellation albumen fluorescence.
[0594] Research in the body of analogue TDT and TDH
[0595] Acute effect:Act on the Abca4 that spends the night to dark adatpation in order to determine that whether TDT and TDH have in the body the visual cycle + /+(Rpe65450Leu, painted, 129/SV XC57BL/6J) the following two kinds of compounds injecting 50mg/kg of mouse single peritonaeum.Give the 13-of injected in mice same concentrations suitable-vitamin A acid (13-RA; Accutane) as a comparison.Inject after one hour mouse photobleaching (5000lux bleaching 2min is with bleaching～90% rhodopsin) and write down ERGs.
[0596] Fig. 5 A shown after staff cell b-wave amplitude photobleaching recovers injected dose be three kinds of compounds (13-RA, TDT and TDH) of 50mg/kg after 1 hour TDT and TDH in animal to the effect of ERG b-wave amplitude.The mean value of getting three mouse in every group as a result of also indicates SD.The ability of two kinds of isoprenoid delay scotopic vision reacting recoveries is similar to 13-RA, and the latter can or use the dark adatpation ERG b-wave amplitude judgement of back light optical recording to draw after photobleaching after the regular interval.Yet still there are the dauer effect (Fig. 5 B) that does not detect 13-RA in TDT and TDH inductive staff cell b-ripple restitution after injecting 3 days.
[0597] in order to determine whether the delay that dark adatpation staff cell b-ripple recovers is because to 11-cis-retinene synthetic effect, we have studied TDT to 11-cis in mouse and the rat-retinene regenerated effect.In rodent, regenerated 11-cis-retinene almost all combines with rhodopsin, so measure the amount [27] that the amount of 11-cis-retinene is equivalent to measure rhodopsin.Preliminary experiment is carried out on Sprague Dawley mouse, so this is owing to carried out using the similar experiment of 13-RA can carry out the contrast [24] of drug effect and effect before on these animals.In these experiments, 13-RA shows by the regeneration of disturbing bleaching back 11-cis-retinene the visual cycle is very obviously acted on [24].Therefore, in present experiment, give rat single injection (under the peritonaeum) TDT (TDH) (the DMSO solution of 50mg/kg), 13-RA (the DMSO solution of 50mg/kg) and only inject DMSO.After the injection analogue, the rat dark adatpation be exposed to then in 2 hours can cause compare with dark adatpation control animal (data not shown) in these animals dark adatpation 11-cis-retinene less than 10% light in.Make the bleaching rat once more after the dark adatpation 30 minutes, with these sacrifice of animal then according to the amount that requires to measure regeneration 11-cis-retinene in the method.In these experiments, measure the chromophoric group of resynthesis 11-cis-retinene and rhodopsin with HPLC, and with alltrans-retinyl ester precursor relatively.
[0598] shown in Fig. 6 A-C, 13-RA (Fig. 6 A) and TDT (Fig. 6 B) remarkable (4-5 doubly) have suppressed the regeneration of 11-cis-retinene, yet the restraining effect of TDH (Fig. 6 C) does not have the restraining effect of TDT obvious.These numerals have shown the HPLC analytical results of the retinoid that the rat of handling from medicine is extracted.Fig. 6 A has shown the HPLC data of the Sprague Dawley rat of handling with 13RA.Fig. 6 A has shown the 11-cis-retinene-cis-oxime of contrast (13-RA) (top) and drug treating animal (bottom) and the relative content of alltrans (cis)-retinyl ester.Fig. 6 .B has shown that TDT handles the related data (top-contrast, bottom-TDT handles mouse) of mouse.In this case, the ester storehouse of drug treating rat is mostly, if all be not, and alltrans.Fig. 6 C has shown that TDH handles the related data (top-contrast, bottom-TDH handles mouse) of rat.These results are with observed to compare TDH with TDT low as the drug effect of mRPE65 antagonist be consistent.Should test and repeat twice again, and on average suppress numerical value and be: 13-RA (78 ± 2%), TDT (79 ± 4%) and TDH (55 ± 2%).These suppress percentages is by comparing (the seeing materials and methods) that obtains with the integral area of the absorption peak of 11-cis-retinene-cis-oxime with retinyl ester.
[0599] it should be noted that in alltrans-retinyl ester storehouse increase (Fig. 6 A-C) on the basis in consumption 11-cis-retinene storehouse under the condition of TDT and TDH existence.Increase the feature that is considered to a kind of mRPE65 antagonist in the time of in this alltrans-retinyl ester storehouse.The inhibition ability of 13-RA approximately identical with the data of report [25].In suppressing, 13-RA is suppressed, so the ester storehouse is 11-cis and alltrans mixture of isomers [22,25] owing to 11-cis-retinol dehydrogenase.Here in the experiment of the use isoprenoid antagonist of Miao Shuing, having only alltrans-retinyl ester is detectable [data not shown].
[0600] in the Balb/c mouse, also carried out using the similar experiment of inhibitor.Also observed restraining effect, but the effect of 13-RA and isoprenoid antagonist not in rat obviously.Inhibiting rate is: 13-RA (33 ± 4%), TDT (35 ± 2%) and TDH (24 ± 6%).It should be noted that 11-cis in the rat-chromophoric regeneration is considerably slower than the regeneration rate [27] in the mouse.Similar to situation in the rat, isoprenoid mRPE65 antagonist and 13RA are almost equivalent to 11 cis-retinene regenerated restraining effect in mouse.
[0601] B) TDT and TDH long-term treatment ABAC4 -/- Mouse is to A 2 The effect of E accumulation: further detect RPE65 antagonist TDT and TDH and reduce RPE lipofuscin fluorophor A 2E and different-A 2The effect of E accumulation.At ABca4 -/-Mouse is (with Abca4 + /+Mouse has identical genetic background) began weekly two kinds of compounds of twice abdominal injection 50mg/kg when big in two months, measure A with quantitative HPLC after two months 2E and different-A 2The level of E.
[0602] shown in Fig. 7 A-D, two kinds of compounds especially TDT can effectively reduce A 2The accumulation of E.Fig. 7 A-D shown Abcr-/-the mouse eyecup in A 2E and different-A 2The quantitative result of E.(A-C) detecting gained reverse hplc typical color spectrogram at the 430nm place has shown A 2E and different-A 2The detection of E is compared with the control animal of vehicle treated, and the peak intensity of TDT and TDH treatment reduces.Fig. 7 D: use the external standard normalization method according to the quantitative A of peak area integration 2E/ is different-A 2E.Numerical value is measured the single sample of collecting from 4 eyes with picomole/eye expression.
[0603] particularly, with the A in the mouse eyecup of TDT processing 2The E level is than the Abca4 that handles with carrier (DMSO) -/-Animal low 85%.So underestimated A because pharmacological agent just begins this result from mouse two months when big 2The reduction degree of E, and this moment is not to A in the knock out mice 2The E accumulation data is carried out calibration.These results show that mRPE65 antagonist TDT and TDH effectively and by restriction visual cycle function slow down A in vivo 2The accumulating rate of E.
[0604] discusses
[0605] PRE65 plays a significant role in the visual cycle and is essential [15] to rhodopsin regeneration.But the vitamin A acid specificity combines with mRPE65 and the isomerization [22] of blocking-up in the RPE film.13RA can limit interior visual cycle [24] this fact of rat body and show that mRPE65 may be as the active target spot that disturbs the toxicity lipofuscin to form.In rat, 13-RA has obvious effect to sight function.After the bleaching 11-cis retinene regenerated is suppressed to reach approximately 4 times [24].This inhibition may be interpreted as Abca4 -/-A in the knock-out mice model 2E series lipofuscin gathers reduction [25].But because vitamin A acid demonstrates the multiple-effect effect, whether can limit the visual cycle with of the inhibition of direct mensuration so we have prepared non--retinoids antagonist of mRPE65, determine that the RPE65 function is the part of visual pigment regeneration rate-limiting step and the accumulation that reduces the retinal toxicity lipofuscin this target spot itself and generation voluntarily.
[0606] we have designed two kinds of non-retinoids antagonists of mRPE65 and have made itself and potent combination of peculiar target spot mRPE65 of visual cycle.TDT and TDH can suppress the regeneration of 11-cis-retinene behind the photobleaching, and the degree with 13-RA is suitable approximately.But different with 13-RA is that TDT and TDH only combine with mRPE65, and the inhibition result shows that this albumen is the operation target spot in the body.The rodent of handling with TDT and TDH can accumulate alltrans-retinyl ester after the mRPE65 blocking-up.This result in the contemplation since when mRPE65 is suppressed alltrans-retinyl ester slower to the conversion of 11-cis-Vogan-Neu.By contrast, the 13-RA accumulation all significantly [24] that has an alltrans and 11 cis retinyl esters down.This is because 13-RA can suppress mRPE65 and 11-cis-retinol dehydrogenase [22,23].
[0607] can significantly suppress A with TDT and TDH long-term treatment 2E is at STGD animal model Abca4 -/-Accumulation in the mouse.Especially TDT is with untreated Abca4 -/-Animal is compared and can stop about 85% A 2E forms, and with A 2The E level reduce to similar age wt animal in the similar level of observed level.The inhibition degree and the A that also need further research that the visual cycle is upgraded 2The relation of E accumulation.This relation is nonlinear probably, and partly cause is A in alltrans retinol at least 2The E accumulation is partial.Also may there be other nonlinear relationship.
[0608], it should be noted that the effect of TDT and TDH is all more lasting than 13-RA, probably because they are more hydrophilic than vitamin A acid according to the pharmacology of isoprenoid mRPE65 antagonist.Hydrophilic increase can slow down the elimination speed of medicine.In addition, extremely strong with the animal that TDT and TDH handle to the tolerance of these compounds, even gave these compounds in per 48 hours and also do not demonstrate tangible toxicity and/or untoward reaction.
[0609] generally speaking, we design and have studied specificity, non-retinoids mRPE65 antagonist, and it can suppress bleaching back 11 cis-retinene regeneration, have verified that further mRPE65 is this hypothesis of a part of visual pigment regeneration rate-limiting step at least.The analogue that the present invention describes can be used for the chemical genetic method of the temporary transient function of mRPE65 in the visual cycle function visual pigment regenerative process.Because the visual cycle is relevant with regulating, can use similar analogue research to belong to the function [19] of sRPE65 together.Except analyzing the external function of RPE65, this non-retinoids antagonist also can obviously suppress macular degeneration Abca4 -/-Lipofuscin A in the mouse model 2The accumulation of E.Our studies show that these compounds or similar molecule may become effective, the nontoxic drug candidate that prevents that lipofuscin responsive type macular degeneration (comprising STGD and the AMD (atrophy of figure shape) [28] that causes a kind of common form of visual deprivation) from taking place.
[0610] document of quoting among the embodiment 1
[0611] 1) .Lamb, T.D etc. (2004) Prog.Retin.Eye Res.23:307-380; 2).Sakmar, T.P. etc. (2002) Ann.Rev.Biophys.and Biomolec.Struct.31:443-484; 3).Rattner, A. etc. (2000) J.Biol.Chem.275:11034-11043; 4).Parish, CA. etc. (1998) Proc.ofthe Natl.Acad, of Sci. (U.S.A.) 95:14609-14613; 5).Sparrow, J.R. etc. (2000) Invest.Ophthalmol.Vis.Sci.41:1981-1989; 6).Mata, N.L. etc. (2000) Proc.Natl.Acad.Sci.U.S.A., 97:7154-7159; 7).Fishkin, N.E. etc. (2005) Proc.Natl.Acad.Sci.U.S.A., 10:, 7091-7096; 8).Allikmets, R. etc. (1997) Nat Genet 15:236-246; 9).Allikmets, R. etc. (1997b) Science 277:1805-1807; 10).Allikmets，R.(2000a)Am?J?Hum?Genet?67：793-799；11)。Beharry, S. etc. (2004) J Biol Chem 279:53972-53979; 12).Weng, J. etc. (1999) Cell 98:13-23; 13).Bavik, CO. etc. (1991) J.Biol.Chem.266:14978-14985; 14).Hamel, CP. etc. (1993) J.Neurosci.Sci.34:414-425; 15).Redmond, T.M. etc. (1998) Nat.Genet.20:344-351; 16).Jahng, WJ. etc. (2003) Biochemistry 42:6159-6168; 17).Gollapalli, D.R. etc. (2003) Biochemistry 42:11824-11830, erratum in:Biochemistry 43:7226 (2003); 18).Mata, N.L. etc. (2004) J.Biol.Chem.279:635-643; 19).Xue, L. etc. (2004) Cell 117:761-771; 20).Kim, S.R. etc. (2004) Proc.Natl.Acad.Sci.USA 101:11668-11672; 21).Lyubarsky, A.L. etc. (2005) Biochemistry 44:9880-9888; 22).Gollapalli, D.R etc. (2004) Proc.Natl.Acad.Sci.U.S.A.101,10030-10035; 23).Law, W.C. etc. (1989) Biochem.Biophys.Res.Commun.161:825-829; 24).Sieving, P.A. etc. (2001) Proc.Natl.Acad.Sci.USA 98:1835-1840; 25).Radu, R.A. etc. (2003) Proc.Natl Acad Sci U S A 100:4742-4747; 26).Guzzo, CA. etc. (1996) in Goodman and Gilman ' s:The Pharmacological Basis ofTherapeutics, 9th Ed, eds.Hardman，J.G.&Limbird，L.E.(McGrawHill，New?York)，pp.1598-1602；27)。Van Hooser, J.P. etc. (2000) Methods in Enzymology, 316:565-575; 28).HoIz, F.G. etc. (2001) Invest.Ophthalmol.Vis.Sci.42,1051-1056; 29).Ma, J. etc. (2001) Invest.Ophthalmol.Vis.Sci.42:1429-1435; 30).Lowry, O.H. etc. (1951) J.Biol.Chem., 193:265-275; And 31).Groenendijk, G.W.T. etc. (1980) Biochim.Biophys.Acta.617:430-438.
[0612] these embodiment do not have any restricted.The content of all reference that are cited (comprise the bibliographic reference quoted everywhere among the application, granted patent, publication application form) all clearly comprises in this application with the reference form.
[0613] those skilled in the art will appreciate that or determine only just can to obtain the equivalence of many specific embodiments of the present invention's description by normal experiment.

Claims (27)

1. the compound of a formula XI:
Wherein, separate when each variable occurs at every turn,
N was 0 to 10 (comprising end points);
R 1Be hydrogen or alkyl;
R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl;
Z be cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl, aralkyl ,-C (=O) R bOr-(CH 2) pR b
P was 0 to 20 (comprising end points);
R aBe hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl;
R bBe hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; With
Figure A20068003723300022
Expression singly-bound or trans double bond;
Condition is that described compound is not that N-(4-hydroxyphenyl) looks yellow acid amides.
2. the compound of claim 1, wherein R 1Be hydrogen or methyl.
3. claim 1 or 2 compound, wherein Z is an aryl.
4. each compound, wherein R among the claim 1-3 aBe hydrogen.
5. the compound of a formula XIa:
Figure A20068003723300023
Wherein, separate when each variable occurs at every turn,
N was 0 to 10 (comprising end points);
R 1Be hydrogen or alkyl;
R 2Be hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl;
R 3, R 4, R 5, R 6And R 7Be hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heteroaralkyl, impure aromatic ene base, hetaryne base, cyano group, nitro, sulfydryl, hydroxyl, alkylsulfonyl, amino, acyl amino, amide group, alkylthio, carboxyl, formamyl, alkoxyl group, sulfonate group, sulfate group, sulfoamido, sulfamyl, alkylsulfonyl or sulfinyl;
R aBe hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl; With
Figure A20068003723300031
Expression singly-bound or trans double bond;
Condition is that described compound is not that N-(4-hydroxyphenyl) looks yellow acid amides.
6. the compound of claim 5, wherein R 1Be hydrogen or methyl.
7. claim 5 or 6 compound, wherein R aBe hydrogen.
8. each compound, wherein R among the claim 5-7 3, R 4, R 6And R 7Be hydrogen.
9. each compound, wherein R among the claim 5-8 5Be hydroxyl.
10. the compound of a formula XIb:
Figure A20068003723300032
Wherein, separate when each variable occurs at every turn,
N was 0 to 5 (comprising end points);
R 1Be hydrogen or methyl;
R 2For hydrogen, alkyl, thiazolinyl, alkynyl, aryl,
Figure A20068003723300041
R 3, R 4, R 5, R 6, R 7And R 8Be hydrogen, halogen, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, aralkyl, arylalkenyl, sweet-smelling alkynyl, heteroaralkyl, impure aromatic ene base, hetaryne base, cyano group, nitro, sulfydryl, hydroxyl, alkylsulfonyl, amino, acyl amino, amide group, alkylthio, carboxyl, formamyl, alkoxyl group, sulfonate group, sulfate group, sulfoamido, sulfamyl, alkylsulfonyl or sulfinyl;
Any two paired R 8With the carbon that combines them can represent C (=O); And R aBe hydrogen, alkyl, cycloalkyl, thiazolinyl, cycloalkenyl group, alkynyl, aryl or aralkyl;
Condition is that described compound is not that N-(4-hydroxyphenyl) looks yellow acid amides.
11. the compound of claim 10, wherein R 1Be hydrogen or methyl.
12. the compound of claim 10 or 11, wherein R aBe hydrogen.
13. each compound, wherein R among the claim 10-12 3, R 4, R 6And R 7Be hydrogen.
14. each compound, wherein R among the claim 10-13 5Be hydroxyl.
15. each compound among the claim 10-14, wherein n was 1 to 3 (comprising end points).
16. each compound, wherein R among the claim 10-15 2For
Figure A20068003723300042
17. each compound, wherein R among the claim 10-15 2For
Figure A20068003723300043
18. each compound, wherein R among the claim 10-15 2For
Figure A20068003723300051
19. the compound of a formula IV:
Figure A20068003723300052
Wherein, separate when each variable occurs at every turn,
N is 1,2,3 or 4.
X is-O-,-NR a-,-C (R b) 2-or-C (=O)-;
Z is-C (=O) R b,-OR b,-N (R b) 2, alkyl or haloalkyl;
R aBe hydrogen, alkyl, haloalkyl, aryl or aralkyl;
And R bBe hydrogen, alkyl, haloalkyl, aryl or aralkyl.
20. the compound of the following structure of tool:
Figure A20068003723300053
21. preparation, comprise the compound of each definition among the claim 1-20 and second compound different with first compound, wherein said second compound is selected from the compound of claim 1-20 or the compound of formula I, II, III, IV, V, VI, VII, VIII, IX or X.
22. each compound is used for the treatment of or prevents purposes in the preparation of ophthalmic diseases in preparation among the claim 1-20.
23. the purposes of mentioning in the claim 22, wherein said ophthalmic diseases are macular degeneration.
24. the purposes of mentioning in the claim 22, wherein said ophthalmic diseases are recessive macular dystrophy.
25. the purposes of mentioning in the claim 22, wherein said ophthalmic diseases are lipofuscin accumulation.
26. the purposes that each is mentioned among the claim 22-25 is wherein used and first kind of second kind of medicine that medicine is different when the preparation said preparation.
27. the purposes of mentioning in the claim 26, wherein a certain step inhibition, antagonism or the short circuit visual cycle of the visual cycle that can outside shaft-like photosensory cell dish, take place of second kind of medicine.
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